Compounds for inflammation and immune-related uses

ABSTRACT

The invention relates to compounds of formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein X, Y, A, Z, L and n are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions and immune disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/611,913, filed Sep. 21, 2004, the contents ofwhich are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to biologically active chemical compounds thatmay be used for immunosuppression or to treat or prevent inflammatoryconditions and immune disorders.

BACKGROUND OF THE INVENTION

Inflammation is a mechanism that protects mammals from invadingpathogens. However, while transient inflammation is necessary to protecta mammal from infection, uncontrolled inflammation causes tissue damageand is the underlying cause of many illnesses. Inflammation is typicallyinitiated by binding of an antigen to T-cell antigen receptor. Antigenbinding by a T-cell initiates calcium influx into the cell via calciumion channels, such as Ca²⁺-release-activated Ca²⁺ channels (CRAG).Calcium ion influx in turn initiates a signaling cascade that leads toactivation of these cells and an inflammatory response characterized bycytokine production.

TRPM4 is a Ca²⁺-actived non-selective (CAN) cation channel that mediatesdepolarization of cellular membranes. Activation of TRPM4 depolarizesthe cellular membrane which decreases the driving force for calcium ioninflux into the cell. Conversely, it has been shown that, inhibition ofTRPM4 channels in T-lymphocytes increases calcium ion influx into thecell and induces large increases in cytokine production and, inparticular, increase the production of interleukin 2 (IL-2).

Kv1.3 is a voltage-dependent potassium ion channel which is selectivelydistributed in T lymphocytes. Activation of Kv1.3 channelshyperpolarizes the cell membrane and facilitates calcium ion influx intothe cell. Inhibition of Kv1.3 is believed to inhibit T-cell activation.It has recently been shown that myelin-reactive T-cells in patients withmultiple sclerosis (MS) exhibit upregulated Kv1.3 expression afteractivation with myelin antigens. Therefore, inhibitors of Kv1.3 channelscould be therapeutically useful in treating MS and other T-cell mediatedautoimmune diseases.

IL-2 is a cytokine that is secreted by T cells in response to calciumion influx into the cell. IL-2 modulates immunological effects on manycells of the immune system. For example, it is a potent T cell mitogenthat is required for the T cell proliferation, promoting theirprogression from G1 to S phase of the cell cycle; it stimulates thegrowth of NK cells; and it acts as a growth factor to B cells andstimulates antibody synthesis.

IL-2, although useful in the immune response, can cause a variety ofproblems. IL-2 damages the blood-brain barrier and the endothelium ofbrain vessels. These effects may be the underlying causes ofneuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue,disorientation and depression. It also alters the electrophysiologicalbehaviour of neurons.

Due to its effects on both T and B cells, IL-2 is a major centralregulator of immune responses. It plays a role in inflammatoryreactions, tumour surveillance, and hematopoiesis. It also affects theproduction of other cytokines, inducing IL-1, TNF-α and TNF-β secretion,as well as stimulating the synthesis of IFN-γ in peripheral leukocytes.

T cells that are unable to produce IL-2 become inactive (anergic). Thisrenders them potentially inert to any antigenic stimulation they mightreceive in the future. As a result, agents which inhibit IL-2 productioncan be used for immunosuppression or to treat or prevent inflammationand immune disorders. This approach has been clinically validated withimmunosuppressive drugs such as cyclosporin, FK506, and RS61443. Despitethis proof of concept, agents that inhibit IL-2 production remain farfrom ideal. Among other problems, efficacy limitations and unwanted sideeffects (including dose-dependant nephrotoxicity and hypertension)hinder their use.

Over-production of proinflammatory cytokines other than IL-2 has alsobeen implicated in many autoimmune diseases. For example, Interleukin 5(IL-5), a cytokine that increases the production of eosinophils, isincreased in patients with asthma. Overproduction of IL-5 is associatedwith accumulation of eosinophils in the asthmatic bronchial mucosa, ahall mark of allergic inflammation. Thus, patients with asthma and otherinflammatory disorders involving the accumulation of eosinophils wouldbenefit from the development of new drugs that inhibit the production ofIL-5.

Interleukin 4 (IL-4) and interleukin 13 (IL-13) have been identified asmediators of the hypercontractility of smooth muscle found ininflammatory bowel disease and asthma. Thus, patients with asthma andinflammatory bowel disease would benefit from the development of newdrugs that inhibit IL-4 and IL-13 production.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a regulatorof maturation of granulocyte and macrophage lineage population and hasbeen implicated as a key factor in inflammatory and autoimmune diseases.Anti-GM-CSF antibody blockade has been shown to ameliorate autoimmunedisease. Thus, development of new drugs that inhibit the production ofGM-CSF would be beneficial to patients with an inflammatory orautoimmune disease.

There is therefore a continuing need for new drugs which overcome one ormore of the shortcomings of drugs currently used for immunosuppressionor in the treatment or prevention of inflammatory disorders andautoimmune disorders. Desirable properties of new drugs include efficacyagainst diseases or disorders that are currently untreatable or poorlytreatable, a new mechanism of action, oral bioavailability and/orreduced side effects.

SUMMARY OF THE INVENTION

This invention meets the above-mentioned needs by providing compoundsthat inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,and IFNγ. These compounds are particularly useful for immunosuppressionand/or to treat or prevent inflammatory conditions and immune disorders.

In one embodiment, the invention relates to compounds represented byformula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

X is an optionally substituted benzoimidazolyl, an optionallysubstituted 5,6,7,8-tetrahydroindolizinyl, an optionally substitutedimidazo[4,5-a]pyridyl, an optionally substituted imidazo[1,2-a]pyridyl,an optionally substituted imidazo[4,5-b]pyridyl, or an optionallysubstituted imidazo[4,5-c]pyridyl;

Y is an unsubstituted alkyl, an optionally substituted alkenyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted aryl, an optionally substitutedheteroaryl, or an optionally substituted heteroaralkyl;

A is —O—, —S(O)_(p)—, —NH—, —NZ—, —CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—,—N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of —N═CH—, —N═CZ—, —CH═N—,or —CZ═N—;

Z, for each occurrence, is independently selected from the groupconsisting of an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo,—OR₄, cyano, nitro, haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄,—NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂;

L is a linker selected from the group consisting of an optionallysubstituted lower alkyl, and optionally substituted lower alkenyl,—NRCR₄R₅—, —C(O)—, —OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—,—C(S)—, —NR—S(O)_(h)—, —S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—,—NR—C(═N—CN)—NR—, —NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or—NR—C(S)—NR—;

R, for each occurrence, is independently selected from —H, an alkyl,acetyl, alkoxycarbonyl, or aralkoxycarbonyl;

R₁ and R₂, for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁ and R₂ taken together with the nitrogen to whichthey are attached is optionally substituted heterocyclyl or optionallysubstituted heteroaryl;

R₄ and R₅ for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

h is 1 or 2;

n is 0 or an integer from 1 to 4; and

p, for each occurrence, is, independently, 0, 1, or 2.

In another embodiment, the invention relates to compounds represented byformula (II):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein:

Y₁ is an alkyl, a heterocyclyl, or an aralkyl, wherein the alkyl,heterocyclyl or aralkyl is optionally substituted with one or moresubstituent selected from the group consisting of an alkyl, an alkynyl,an cycloalkyl, an cycloalkenyl, an heterocyclyl, an aryl, anheteraralkyl, a haloalkyl, —C(O)NH₂, —NR₄C(O)R₅, halo, —OR₄, cyano,nitro, haloalkoxy, —C(O)R₄, —NR₁R₂, —SR₄, —C(O)OH, —OC(O)R₄,—NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂;and

X, R₁, R₂, R₄, R₅, A, L, Z, h, n and p are defined as for formula (I).

In another embodiment, the invention relates to compounds represented byformula (III):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein:

R₆, for each occurrence, and R₇ are, independently, selected from thegroup consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, a haloalkyl, —C(O)NR₁R₂,—NR₄C(O)R₅, halo, —OR₄, cyano, nitro, haloalkoxy, —C(O)R₄, —NR₁R₂,—C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅,—S(O)_(p)R₄, or —S(O)_(h)R₁R₂;

m is 0 or an integer from 1 to 4; and

Y, R₁, R₂, R₄, R₅, A, L, Z, h, n and p are defined as for formula (I).

-   -   In another embodiment, the invention relates to compounds        represented by formula (IV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein t is 0 or an integer from 1 to 8; Y, A, Z, and n aredefined as in formula (I); and R₆ and R₇ are defined as in formula(III).

In another embodiment, the invention relates to compounds represented byformula (V):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y, L, A, Z, and n are defined as in formula (I); and R₆,R₇ and m are defined as in formula (III).

In another embodiment, the invention relates to compounds represented byformula (VI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein:

one of X₂, X₃, X₄, or X₅ is N and the others are, independently, CH orCR₆,

q is 0 or an integer from 1 to 3;

Y, L, A, Z, and n are defined as in formula (I); and

R₆ and R₇ are defined as in formula (III).

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful inhibitingimmune cell (e.g., T-cells, B-cells and/or mast cells) activation (e.g.,activation in response to an antigen). In particular, a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof can inhibit immune cell proliferation and inhibit theproduction of certain cytokines that regulate immune cell activation.For example, a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof can inhibit theproduction of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, INF-γ andcombinations thereof. Moreover, a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrug thereofcan modulate the activity of one or more ion channel involved inactivation of immune cells, such as CRAC, TRPM4, and Kv1.3 ion channels.

A compound of the invention or a pharmaceutically acceptable salt,solvate, clathrate, or prodrug thereof is particularly useful forimmunosuppression or for treating or preventing inflammatory conditions,immune disorders or allergic disorders.

The invention also encompasses pharmaceutical compositions comprising aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof; and apharmaceutically acceptable carrier or vehicle. These compositions mayfurther comprise additional agents. These compositions are useful fortreating or preventing inflammatory conditions, immune disorders andallergic disorders.

The invention further encompasses methods for treating or preventinginflammatory conditions, immune disorders and allergic disorders,comprising administering to a subject in need thereof a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof, or a pharmaceutical composition comprising a compoundof the invention or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof. These methods may also compriseadministering to the subject an additional agent separately or in acombination composition with the compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

The invention further encompasses methods for suppressing the immunesystem of a subject, comprising administering to a subject in needthereof a compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, or a pharmaceuticalcomposition comprising a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof. These methodsmay also comprise administering to the subject an additional agentseparately or in a combination-composition with the compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

The invention further encompasses methods for inhibiting immune cellactivation, including inhibiting proliferation of immune cells (e.g., Tcells, B cells and/or mast cells), in vivo or in vitro using aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof or apharmaceutical composition comprising an effective amount of a compoundof the invention or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof.

The invention further encompasses methods for inhibiting cytokineproduction, (e.g., IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, and/or INF-γproduction) in vivo or in vitro using an effective amount of a compoundof the invention or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof or a pharmaceutical composition comprisingan effective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof.

The invention further encompasses methods for modulating ion channelactivity, and in particular, modulating the activity of ion channelsinvolved in immune cell activation (e.g., CRAC, TRPM4, and/or Kv1.3), invivo or in vitro using an effective amount of a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof or a pharmaceutical composition comprising an effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof.

All of the methods of this invention may be practice with a compound ofthe invention alone, or in combination with other agents, such as otherimmunosuppressive, anti-inflammatory or immune disorder agents.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term an “aromatic ring” or “aryl” means a monocyclicor polycyclic-aromatic ring or ring radical composed of carbon andhydrogen atoms. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, andnaphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationalkyl (preferably, lower alkyl), haloalkyl (preferably trifluoromethyl),hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl (preferably, alower alkylsulfanyl), cyano, halo, amino, and nitro. In certainembodiments, the aryl group is a monocyclic ring, wherein the ringcomprises 6 carbon atoms.

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon typically having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while saturated branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl; 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkylgroups included in compounds of this invention may be optionallysubstituted with one or more substituents, such as amino, alkylamino,alkoxy, alkylsulfanyl, arylsulfanyl, halo, acyl, nitro, hydroxyl, cyano,aryl, aralkyl, aryloxy, arylthio, arylamino, carbocyclyl,carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylthio, and the like. Inaddition, any carbon in the alkyl segment may be substituted with oxygen(═O), sulfur (═S), or nitrogen (═NR²³, wherein R²³ is —H, an alkyl,acetyl, or aralkyl). Lower alkyls are typically preferred for thecompounds of this invention.

The term alkylene refers to an alkyl or cycloalkyl group that has atleast two points of attachment to at least two moieties (e.g., {—CH₂—},—{CH₂CH₂—},

etc., wherein the brackets indicate the points of attachment). Alkylenegroups may be substituted or unsubstituted.

The term “aralkyl” or “arylalkyl,” as used herein, refers to an arylgroup that is attached to another moiety via an alkylene linker. Aralkylgroups can be substituted or unsubstituted.

The term “alkoxy,” as used herein, refers to an alkyl group which islinked to another moiety though an oxygen atom. Alkoxy groups can besubstituted or unsubstituted.

As used herein, the term “alkenyl” means an alkyl radical typicallyhaving from 2 to 10 carbon atoms and having at least one carbon-carbondouble bond. Representative straight chain and branched alkenyls includevinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl,2-pentenyl, 3-methyl-1-butenyl, -methyl-2-butenyl,2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl,2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl,2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like.Alkenyl groups can be substituted or unsubstituted.

As used herein, the term “alkynyl” means an alkyl radical typicallyhaving from 2 to 10 carbon atoms and having at lease one carbon-carbontriple bond. Representative straight chain and branched alkynyls includeacetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1-butynyl, 4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl,1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl,1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and thelike. Alkynyl groups can be substituted or unsubstituted.

As used herein, the term “cycloalkyl” means a saturated cyclic alkylradical typically having from 3 to 10 carbon atoms. Representativecycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Cycloalkyl groupscan be substituted or unsubstituted.

As used herein, the term “bicycloalkyl” means a bi-cyclic alkyl systemtypically having from 8 to 14 carbon atoms and at least one saturatedcyclic alkyl ring. Representative bicyclocycloalkyls includedecahydronaphthyl, adamantyl, bicycle[4.3.3]dodecyl, and the like.Bicycloalkyl groups can be substituted or unsubstituted.

As used herein, the term “cycloalkenyl” means a cyclic non-aromaticalkenyl radical having at least one carbon-carbon double bond in thecyclic system and typically having from 5 to 10 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be substituted orunsubstituted.

As used herein, the term “carbocycle” or “carbocyclyl” referscollectively to cycloalkyls, cycloalkenyls, and bicycloalkyls. Acarbocycle can be substituted or unsubstituted.

As used herein, the term “heterocycle” or “heterocyclyl” means amonocyclic (typically having 3- to 10-members) or a polycyclic(typically having 8- to 14-members) heterocyclic ring which is either asaturated ring or a unsaturated non-aromatic ring. A 3- to 10-memberedheterocycle can contain up to 5 heteroatoms; and a 8- to 14-memberedheterocycle can contain up to 6 heteroatoms. Typically, a heterocyclehas at least on carbon atom ring member. Each heteroatom isindependently selected from nitrogen, which can be oxidized (e.g.,N(O))quaternized; oxygen; and sulfur, including sulfoxide and sulfone.The heterocycle may be attached via any heteroatom or carbon atom.Representative heterocycles include morpholinyl, thiomorpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatommay be substituted with a protecting group known to those of ordinaryskill in the art, for example, the hydrogen on a nitrogen may besubstituted with a tert-butoxycarbonyl group. Furthermore, theheterocyclyl may be optionally substituted with one or more substituents(including without limitation a halogen atom, an alkyl radical, or arylradical). Only stable isomers of such substituted heterocyclic groupsare contemplated in this definition. Heterocyclyl groups can besubstituted or unsubstituted.

As used herein, the term “heteroaromatic” or “heteroaryl” means amonocyclic (typically having 5- to 10-members) or polycyclic (typicallyhaving 8- to 14-members) heteroaromatic ring (or radical thereof)comprising carbon atom ring members and one or more heteroatom ringmembers, such as, for example, oxygen, sulfur (including S(O) and S(O)₂)or nitrogen (including N(O) or quaternized nitrogen). In one embodiment,the heteroaromatic ring is selected from 5-8 membered heteroaryl rings.In another embodiment, the heteroaromatic ring is a 5 or 6 memberedring. In another embodiment, the heteroaromatic ring has from 1 to about4 heteroatoms selected from oxygen, sulfur and nitrogen. Representativeheteroaryls include pyridyl, furanyl, thiophenyl, pyrrolyl, oxazolyl,imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl,thiadiazolyl, pyrazinyl, quinolyl, isoquinolinyl, indazolyl,benzoxazolyl, benzo[1,3]dioxolyl, benzofuryl, benzothiazolyl,imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl,indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, [1,2,3]thiadiazolyl, 5,6,7,8-tetrahydroindolizinyl,imidazo[4,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b[pyridyl,imidazo[4,5-c]pyridyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl orbenzo(b)thienyl and the like. These heteroaryl groups may be optionallysubstituted with one or more substituents including (but not limited toamino, alkylamino, alkoxy, alkylthio, oxo, halo, acyl, nitro, hydroxyl,cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl,carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylthio, and the like.Particular heteroaryl substituents include halo, lower cyano, haloalkyl,lower alkoxy, lower alkyl, hydroxyl, amino, lower alkylsulfanyl,—C(O)O-(lower alkyl), —C(O)NH₂, —OC(O)-(lower alkyl), and —C(O)-(loweralkyl).

The term “heteroaralkyl” or “heteroarylalkyl,” as used herein, refers toa heteroaryl group that is attached to another moiety via an alkylenelinker. Heteroaralkyl groups can be substituted or unsubstituted.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CHICH₃, andthe like.

As used herein, the term “haloalkoxy” or “haloalkyloxy” means an alkoxygroup in which one or more —H is replaced with a halo group. Examples ofhaloalkoxy groups include —OCF₃ and —OCHF₂.

As used herein, the term “alkoxycarbonyl” means a group having theformula —C(O)O-(alkyl). An example of an alkoxycarbonyl ist-butoxycarbonyl.

As used herein, the term “aralkoxycarbonyl” means a group having theformula —C(O)O-(aralkyl). An example of an aralkoxycarbonyl isbenzyloxycarbonyl.

As used herein, the terms “subject”, “patient” and “animal”, are usedinterchangeably and include, but are not limited to, a cow, monkey,horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit,guinea pig and human. The preferred subject, patient or animal is ahuman.

As used herein, the term “lower” refers to a group having up to fouratoms. For example, a “lower alkyl” refers to an alkyl radical havingfrom 1 to 4 carbon atoms, a “lower alkenyl” or “lower alkynyl” refers toan alkenyl or alkynyl radical having from 2 to 4 carbon atoms, and alower alkoxy refers to an alkoxy having from 1 to 4 carbon atoms. Lowersubstituents are typically preferred.

Where a particular substituent occurs multiple times in a givenstructure or moiety, the identity of the substituent is independent ineach case and may be the same as or different from other occurrences ofthat substituent in the structure or moiety. Furthermore, individualsubstituents in the specific embodiments and exemplary compounds of thisinvention are preferred in combination with other such substituents inthe compounds of this invention, even if such individual substituentsare not expressly noted as being preferred or not expressly shown incombination with other substituents.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Were a compound is referred to by botha chemical structure and a chemical name, and the chemical structure andchemical name conflict, the chemical structure is determinative of thecompound's identity.

Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl groups include any substituent which will form a stablecompound of the invention. Examples of substituents for an alkyl,alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,aryl, aralkyl, heteroaryl, and heteroarylalkyl include an alkyl, analkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, an heterocyclyl, anaryl, an heteroaryl, an aralkyl, an heteraralkyl, a haloalkyl,—C(O)NR₁R₂, —NR₄C(O)R₅, halo, —OR₄, cyano, nitro, haloalkoxy, C(O)R₄,—NR₁R₂, —C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅,—S(O)_(p)R₄, or —S(O)_(h)NR₁R₂, wherein R₁, R₂, R₄, R₅, h and p are asdefined above.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₄.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as (without limitation) carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one or more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for hydroxy include benzyl, methoxymethyl and thelike. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of any one of formulas (I) through (XVII),Table 1 or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof and also include protected derivatives thereof.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, but they may have activity intheir unreacted forms. Examples of prodrugs contemplated in thisinvention include, but are not limited to, analogs or derivatives ofcompounds of any one of formulas (I) through (XVII), or Table 1 thatcomprise biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. Other examples of prodrugs include derivatives of compoundsof any one of formulas (I) through (XVII), or Table 1 that comprise —NO,—NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically be prepared usingwell-known methods, such as those described by 1 BURGER'S MEDICINALCHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolffed., 5^(th) ed), the entire teachings of which are incorporated hereinby reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either. 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas (I) through (XVII) or Table 1. Illustrative salts include,but are not limited, to sulfate, citrate, acetate, oxalate, chloride,bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate; methanesulfonate, ethanesulfonate;benzenesulfonate, p-toluenesulfonate; and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of formulas (I) through (XVII) or Table 1 having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically, acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl-N-ethylamine, diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas (I) through(XVII) or Table 1. The term solvate includes hydrates (e.g.,hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and thelike).

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein, the term “asthma” means a pulmonary disease, disorder orcondition characterized by reversible airway obstruction, airwayinflammation, and increased airway responsiveness to a variety ofstimuli.

“Immunosuppression” refers to impairment of any component of the immunesystem resulting in decreased immune function. This impairment may bemeasured by any conventional means including whole blood assays oflymphocyte function, detection of lymphocyte proliferation andassessment of the expression of T cell surface antigens. The antisheepred blood cell (SRBC) primary (IgM) antibody response assay (usuallyreferred to as the plaque assay) is one specific method. This and othermethods are described in Luster, M. I., Portier, C., Pait, D. G., White,K. L., Jr., Gennings, C., Munson, A. E., and Rosenthal, G. J. (1992).“Risk Assessment in Immunotoxicology I: Sensitivity and Predictabilityof Immune Tests.” Fundam. Appl. Toxicol., 18, 200-210. Measuring theimmune response to a T-cell dependent immunogen is another particularlyuseful assay (Dean, J. H., House, R. V., and Luster, M. I. (2001).“Immunotoxicology: Effects of, and Responses to, Drugs and Chemicals.”In Principles and Methods of Toxicology: Fourth Edition (A. W. Hayes,Ed.), pp. 1415-1450, Taylor & Francis, Philadelphia, Pa.). Subjects inneed of immunosuppression include subjects who are about to undergo orhave undergone organ transplantation, including kidney, heart, lung,liver, intestines, bone marrow, skin grafts and transplantation ofislets of Langerhans, or subjects that have immune, inflammatory orallergic disorders.

The compounds of this invention can be used to treat subjects withimmune disorders. As used herein, the term “immune disorder” and liketerms means a disease, disorder or condition caused by the immune systemof an animal, including autoimmune disorders. Immune disorders includethose diseases, disorders or conditions that have an immune componentand those that rare substantially or entirely immune system-mediated.Autoimmune disorders are those wherein the animal's own immune systemmistakenly attacks itself, thereby targeting the cells, tissues, and/ororgans of the animal's own body. For example, the autoimmune reaction isdirected against the brain in multiple sclerosis and the gut in Crohn'sdisease in other autoimmune disorders such as systemic lupuserythematosus (lupus), affected tissues and organs may vary amongindividuals with the same disease. One person with lupus may haveaffected skin and joints whereas another may have affected skin, kidney,and lungs. Ultimately, damage to certain tissues by the immune systemmay be permanent, as with destruction of insulin-producing cells of thepancreas in Type 1 diabetes mellitus. Specific autoimmune disorders thatmay be ameliorated using the compounds and methods of this inventioninclude without limitation, autoimmune disorders of the nervous system(e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathiessuch as Guillain-Barré, and autoimmune uveitis), autoimmune disorders ofthe blood (e.g., autoimmune hemolytic anemia, pernicious anemia, andautoimmune thrombocytopenia), autoimmune disorders of the blood vessels(e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides suchas Wegener's granulomatosis, and Behcet's disease), autoimmune disordersof the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigusvulgaris, and vitiligo), autoimmune disorders of the gastrointestinalsystem (e.g., Crohn's disease, ulcerative colitis, primary biliarycirrhosis, and autoimmune hepatitis), autoimmune disorders of theendocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus,Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis andorchitis, and autoimmune disorder of the adrenal gland); and autoimmunedisorders of multiple organs (including connective tissue andmusculoskeletal system diseases) (e.g, rheumatoid arthritis, systemiclupus erythematosus, scleroderma, polymyositis, dermatomyositis,spondyloarthropathies such as ankylosing spondylitis, and Sjogren'ssyndrome). In addition, other immune system mediated diseases, such asgraft-versus-host disease and allergic disorders, are also included, inthe definition of immune, disorders herein. Because a number of immunedisorders are caused by inflammation, there, is some overlap betweendisorders that are considered immune disorders and inflammatorydisorders. For the purpose of this invention, in the case of such anoverlapping disorder, it may be considered either an immune disorder oran inflammatory disorder. “Treatment of an immune disorder” hereinrefers to administering a compound or a composition of the invention toa subject, who has an immune disorder, a symptom of such a disease or apredisposition towards such a disease, with the purpose to cure,relieve, alter, affect, or prevent the autoimmune disorder, the symptomof it, or the predisposition towards it.

As used herein, the term “allergic disorder” means a disease, conditionor disorder associated with an allergic response against normallyinnocuous substances. These substances may be found in the environment(such as indoor air pollutants and aeroallergens) or they may benon-environmental (such as those causing dermatological or foodallergies). Allergens can enter the body through a number of routes,including by inhalation, ingestion, contact with the skin or injection(including by insect sting). Many allergic disorders are linked toatopy, a predisposition to generate the allergic antibody IgE. BecauseIgE is able to sensitize mast cells anywhere in the body, atopicindividuals often express disease in more than one organ. For thepurpose of this invention, allergic disorders include anyhypersensitivity that occurs upon re-exposure to the sensitizingallergen, which in turn causes the release of inflammatory mediators.Allergic disorders include without limitation, allergic rhinitis (e.g.,hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitismedia, drug reactions, insect sting reactions, latex reactions,conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions,atopic dermatitis, asthma and food allergies.

The compounds of this invention can be used to prevent or to treatsubjects with inflammatory disorders. As used herein, an “inflammatorydisorder” means a disease, disorder or condition characterized byinflammation of body tissue or having an inflammatory component. Theseinclude local inflammatory responses and systemic inflammation.Examples, of such inflammatory disorders include: transplant rejection;chronic inflammatory disorders of the joints, including arthritis,rheumatoid arthritis, osteoarthritis and bone diseases associated withincreased bone resorption; inflammatory bowel diseases such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung disorders such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory disordersof the eye including corneal dystrophy, trachoma, onchocerciasis,uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory disorders of the gums, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney including uremic complications, glomerulonephritis and nephrosis;inflammatory disorders of the skin including sclerodermatitis, psoriasisand eczema; inflammatory diseases of the central nervous system,including chronic demyelinating diseases of the nervous system, multiplesclerosis, AIDS-related neurodegeneration and Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune disorders, immune-complexvasculitis, systemic lupus and erythematodes; systemic lupuserythematosus (SLE); and inflammatory diseases of the heart such ascardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis); as well as various other diseases with significantinflammatory components, including preeclampsia; chronic liver failure,brain and spinal cord trauma, cancer). There may also be a systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent used in cancer chemotherapy.“Treatment of an inflammatory disorder” herein refers to administering acompound or a composition of the invention to a subject, who has aninflammatory disorder, a symptom of such a disorder or a predispositiontowards such a disorder, with the purpose to cure, relieve, alter,affect, or prevent the inflammatory disorder, the symptom of it, or thepredisposition towards it.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a subject oralternatively, the quantity of compound that possess a desired activityin-vivo or in-vitro. In the case of inflammatory disorders, allergicdisorders and autoimmune disorders, a beneficial clinical outcomeincludes reduction in the extent or severity of the symptoms associatedwith the disease or disorder and/or an increase in the longevity and/orquality of life of the subject compared with the absence of thetreatment. The precise amount of compound administered to a subject willdepend on the type and severity of the disease or condition and on thecharacteristics of the subject, such as general health, age, sex, bodyweight and tolerance to drugs. It will also depend on the degree,severity and type of inflammatory disorder or autoimmune disorder,allergic disorders, or the degree of immunosuppression sought. Theskilled artisan will be able to determine appropriate dosages dependingon these and other factors.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' geometric isomers, enantiomers andstereoisomers, that is, both the stereomerically pure form (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and enantiomeric, diastereomeric, and geometric isomeric mixtures. Insome cases, one enantiomer, diastereomer, or geometric isomer willpossess superior activity or an improved toxicity or kinetic profilecompared to others. In those cases, such enantiomers, diastereomers, andgeometric isomers of a compound of this invention is preferred.

The term “inhibit production of IL-2” and like terms means inhibitingIL-2 synthesis (e.g. by inhibiting transcription (mRNA expression), ortranslation (protein expression)) and/or inhibiting IL-2 secretion in acell that has the ability to produce and/or secrete IL-2 (e.g., Tlymphocyte). Likewise, the term “inhibiting production of IL-2, IL-4,IL-5, IL-13, GM-CSF, TNF-α or INF-γ means inhibiting the synthesis (e.g.by inhibiting transcription, or translation) and/or inhibiting thesecretion in a cell that has the ability to produce and/or secrete thesecytokines.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20%® by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of any one of formulas(I) through (XVII) or Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are typically administeredin isolated form or as the isolated form in a pharmaceuticalcomposition. As used herein, “isolated” means that the compounds of theinvention are separated from other components of either (a) a naturalsource, such as a plant or cell, preferably bacterial culture, or (b) asynthetic organic chemical reaction mixture. Preferably, viaconventional techniques, the compounds of the invention are purified. Asused herein, “purified” means that when isolated, the isolate containsat least 95%, preferably at least 98%, of a single compound of theinvention by weight of the isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and, combinations willbe apparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

SPECIFIC EMBODIMENTS

The invention relates to compounds and pharmaceutical compositions thatare particularly useful for immunosuppression or to treat or preventinflammatory conditions and immune disorders.

One embodiment of the invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

X is an optionally substituted benzoimidazolyl, an optionallysubstituted 5,6,7,8-tetrahydroindolizinyl, an optionally substitutedimidazo[4,5-a]pyridyl, an optionally substituted imidazo[1,2-a]pyridyl,an optionally substituted imidazo[4,5-b]pyridyl, or an optionallysubstituted imidazo[4,5-c]pyridyl;

Y is an unsubstituted alkyl, an optionally substituted alkenyl, anoptionally, substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted aryl, an optionally substitutedheteroaryl, or an optionally substituted heteroaralkyl;

A is —O—, —S(O)_(p)—, —NH—, —NZ—, —CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—,—N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of —N═CH—, —N═CZ—, —CH═N—,or —CZ═N—;

Z, for each occurrence, is independently selected from the groupconsisting of an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo,—OR₄, cyano, nitro, haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄,—NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁,R₂;

L is a linker selected from the group consisting of an optionallysubstituted lower alkyl, and optionally substituted lower alkenyl,—NRCR₄R₅—, —C(O)—, —OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—,—C(S)—, —NR—S(O)_(h)—, —S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—,—NR—C(═N—CN)—NR—, —NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or—NR—C(S)—NR—;

R, for each occurrence, is independently selected from —H, an alkyl,acetyl, alkoxycarbonyl, or aralkoxycarbonyl;

R₁ and R₂, for each occurrence are, independently, H, an optionallysubstituted alkyl; an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁ and R₂ taken together with the nitrogen to whichthey are attached is optionally substituted heterocyclyl or optionallysubstituted heteroaryl;

R₄ and R₅ for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

h is 1 or 2;

n is 0 or an integer from 1 to 4; and

p, for each occurrence, is, independently, 0, 1, or 2.

In another embodiment, the invention relates to compounds represented byformula (II):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein:

Y₁ is an alkyl, a heterocyclyl, or an aralkyl, wherein the alkyl,heterocyclyl or aralkyl is optionally substituted with one or moresubstituent selected from the group consisting of an alkyl, an alkynyl,an cycloalkyl, an cycloalkenyl, an heterocyclyl, an aryl, anheteraralkyl, a haloalkyl, —C(O)NH₂, —NR₄C(O)R₅, halo, —OR₄, cyano,nitro, haloalkoxy, —C(O)R₄, —NR₁R₂, —SR₄, —C(O)OH, —OC(O)R₄,—NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂;and

X, R₁, R₂, R₄, R₅, A, L, Z, h, n and p are defined as for formula (I).

In another embodiment, the invention relates to compounds represented byformula (III):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein:

R₆, for each occurrence, and R₇ are, independently, selected from thegroup consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, a haloalkyl, —C(O)NR₁R₂,—NR₄C(O)R₅, halo, —OR₄, cyano, nitro, haloalkoxy, —C(O)R₄, —C(O)OR₄,—OC(O)R₄, —NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or—S(O)_(h)NR₁R₂;

m is 0 or an integer from 1 to 4; and

Y, R₁, R₂, R₄, R₅, A, L, Z, h, n and p are defined as for formula (I).

In another embodiment, the invention relates to compounds represented byformula (XII)

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein X₁ is N, CH or CZ; Y, L, Z, and n are defined as forformula (I); and R₆, R₇ and m are defined as in formula (III).

In another embodiment, the invention relates to compounds represented byformula (VII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y and L are defined as for formula (I); and R₆ and R₇are defined as for formula (III).

In another embodiment, the invention relates to compounds represented byformula (VIII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein:

R₈, for each occurrence, is, independently, selected from the groupconsisting of an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo,—OR₁, cyano, nitro, haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄,—NR₄C(O)NR₁R₂, —OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂;and

r is 0 or an integer from 1 to 5;

Z, R₁, R₂, R₄, R₅, h, n, and p are defined as for formula (I); R₆, R₇and m are defined as for formula (III); and X₁ is defined as in formula(XII).

In another embodiment, the invention relates to compounds represented byformula (IX):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein R₆, and R₇ are defined as for formula (III); and R₈ andr are defined as in formula (VIII).

In another embodiment, the invention relates to compounds represented byformula (XVI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Z and n are defined as for formula (I); R₆, R₇ and m aredefined as for formula (III); X₁ is defined as in formula (XII); and R₈and r are defined as in formula (VIII).

In another embodiment, the invention relates to compounds represented byformula (XVII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein R₆, R₇ and m are defined as for formula (III); and R₈and r are defined as in formula (VIII).

In another embodiment, the invention relates to compounds represented byformula (IV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein t is 0 or an integer from 1 to 8; A, Z, and n aredefined as for formula (I); and R₆ and R₇ are defined as for formula(III).

In another embodiment, the invention relates to compounds represented byformula. (XIII):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y, L, Z, and n are defined as for formula (I); R₆ and R₇are defined as in formula (III); X₁ is defined as in formula (XII); andt is defined as in formula (IV).

In another embodiment, the invention relates to compounds represented byformula (X).

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y is defined as for formula (I); and R₇ is defined asfor formula (III).

In another embodiment, the invention relates to compounds represented byformula (V):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y, L, A, Z, and n are defined as in formula (I); and R₆,R₇ and m are defined as in formula (III).

In another embodiment, the invention relates to compounds represented byformula (XIV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y, L, Z, and n are defined as in formula (I); R₆, R₇,and m are defined as for formula (III); and X₁ is defined as in formula(XII).

In one embodiment, the invention relates to compounds represented byformula (XI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y is defined as in formula (I); and R₇ is defined as informula (III).

In another embodiment, the invention relates to compounds represented byformula (VI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein:

one of X₂, X₃, X₄, or X₅ is N and the others are, independently, CH orCR₆;

q is 0 or an integer from 1 to 3;

Y, L, A, Z, and n are defined as in formula (I); and R₆ and R₇ aredefined as in formula (III).

In another embodiment, the invention relates to compounds represented byformula (XV):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof wherein Y, L, Z, and n are defined as for formula (I); R₆ and R₇are defined as for formula (III); X₁ is defined as for formula (XII);and X₂, X₃, X₄, X₅ and q are defined as for formula (VI).

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   2,3,6-Trifluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3,5-Trifluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3,4-Trifluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Methyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-isonicotinamide;-   3-Fluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-isonicotinamide;-   2,4-Dichloro-5-fluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide,-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   2,4-Difluoro-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Nitro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-methylsulfanyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-thiobenzamide;-   2,3-Dichloro-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-6-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-Fluoro-2-chloro-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3,6-Trifluoro-5-amino-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[3-methyl-4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-Methyl-N-[4-(2-trifluoromethyl-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-6-cyano-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-4-amino-benzoimidazol-1-yl)-phenyl]-benzamide;-   N-(3-{N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-carbamoyl}-2,4,5-trifluoro-phenyl)-carbamic    acid t-butyl ester;-   2,3-Difluoro-N-[4-(2-chloro-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    {N-[4-(2-chloro-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]}amide;-   2,3-Difluoro-N-[2-chloro-4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Difluoro-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Fluoro-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-isonicotinamide;-   2,3-Difluoro-N-[4-(2-bromo-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    {N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]}amide;-   2,3-Difluoro-N-[3-trifluoromethyl-4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   N-(4-{N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-carbamoyl}-2,3-difluoro-phenyl)-carbamic    acid t-butyl ester;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5,6-dimethoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-iodo-benzoimidazol-1-yl)-phenyl]-benzamide;-   N′-[2-(2-trifluoromethyl-benzoimidazol-1-yl)-pyrid-5-yl]-N-(2,5-difluoro-phenyl)-thiourea;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-tert-butyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[2-(2-trifluoromethyl-benzoimidazol-1-yl)-pyrid-3-yl]-benzamide;-   2,3-Difluoro-N-[3-cyano-4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Difluoro-N-[3-chloro-4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-amino-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-methanesulfinyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Difluoro-N-[2-(2-trifluoromethyl-benzoimidazol-1-yl)-pyrid-5-yl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5,6-dimethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-4-amino-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-imidazo[4,5-b]pyrid-3-yl)-phenyl]-benzamide;-   N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-nicotinamide;-   N-(2,3-difluorophenyl)-4-(2-trifluoromethyl-benzoimidazol-1-yl)-benzamide;-   1-(2,3-difluoro-phenyl)-3-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-acrylonitrile;-   -(2,5-difluoro-phenyl)-3-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-acrylonitrile;-   2,3-Difluoro-N-[4-(2-isopropyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   N′-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-N-(2,5-difluoropheyl)-urea;-   1-Oxo-3-fluoro-N-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-isonicotinamide;-   2,3-Difluoro-N-[4-(trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzenesulfonamide;-   2,3-Difluoro-N-[3-acetylamino-4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[2-methyl-4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Difluoro-N-[4-(2-trifluoromethyl-imidazo[4,5-b]pyrid-3-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-{4-[2-trifluoromethyl-5-(1,3-dioxo-isoindol-2-yl)-benzoimidazol-1-yl]-phenyl}-benzamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    {N-[4-(2-trifluoromethyl-imidazo[4,5-b]pyrid-3-yl)-phenyl]}amide;-   2,3-Difluoro-N-[4-(2-methyl-benzoimidazol-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5,6-dihydroxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-imidazo[4,5-c]pyrid-1-yl)-phenyl]-benzamide;-   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid    {N-[2-(2-(2-trifluoromethyl-benzoimidazol-1-yl)-pyrid-5-yl]}amide;-   2,4,6-Trichloro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-{-4-[2,5-di-(trifluoromethyl)-benzoimidazol-1-yl]-phenyl}-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-methanesulfonyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Butyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Difluoro-N-{4-[2-trifluoromethyl-5-(5-tert-butyl-oxazol-2-yl)-benzoimidazol-1-yl]-phenyl}-benzamide;-   2,3-Difluoro-N-{4-[2-trifluoromethyl-5-(5-tert-butyl-oxazol-2-yl)-benzoimidazol-1-yl]-phenyl}-benzamide;-   Furan-2-carboxylic acid    (N-{4-[2-trifluoromethyl-5-(5-tert-butyl-oxazol-2-yl)-benzoimidazol-1-yl]-phenyl})amide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide;-   2,3,4,5-Tetrafluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Phenyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Iodo-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   Naphthalene-2-carboxylic acid    {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]}amide;-   Benzo[1,3]dioxole-5-carboxylic acid    {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]}amide;-   4-Methyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Cyano-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Nitro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Ethyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Trifluoromethyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3,5-Dinitro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-butyramide;-   Naphthalene-1-carboxylic acid    {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]}amide;-   3-Methyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-but-2-enoic    acid amide;-   4-Propyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   Thiophene-2-carboxylic acid    {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]}amide;-   2-Ethyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-hexanoic    acid amide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-heptanoic    acid amide;-   3-Methoxy-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-Phenyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-cyclopropanecarboxylic    acid amide;-   3-Trifluoromethyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-(4-Methoxy-phenyl)-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-acetamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-6-acetylamino-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-(Thien-2-yl)-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-acetamide;-   2-phenyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-acetamide;-   2-Trifluoromethyl-1-[4-(2,3-difluoro-benzoylamimo)-phenyl]-1H-benzoimidazole-5-carboxylic    acid methyl ester,-   2,3,4,5,6-Pentafluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,4-Difluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-hydroxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Difluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Cyano-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,6-Dichloro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3,5-Dichloro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-Bromo-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-cyclopentanecarboxylic    acid amide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-cyclohexanecarboxylic    acid amide;-   2-Nitro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide,-   4-Chloro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Chloro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3,4-Difluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-isopropoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-carbamoyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-isonicotinamide;-   2-Iodo-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Methyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-butyramide;-   3,5-Dichloro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Bromo-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   4-Bromo-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   Furan-2-carboxylic acid    {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]}-amide;-   1-(2,2,2-Trifluoroacetyl)-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-pyrrolidine-2-carboxylic    acid amide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-acrylamide;-   2-Benzyloxy-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-acetamide;-   2-Phenylsulfanyl-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-acetamide;-   N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-succinamic    acid ethyl ester;-   2-Chloro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Di-(trifluoromethyl)-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-Methoxy-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3,5-Di-(trifluoromethyl)-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,5-Dimethoxy-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-(3,4-dimethoxy-phenyl)-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-acetamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-acetoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,3-Difluoro-N-[4-(2-trifluoromethyl-5-acetyl-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,6-Difluoro-N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]-benzylamine;-   N-[4-(5-Chloro-2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-N-(2,3-difluoro-benzoyl)-2,3-difluoro-benzamide;-   N-[4-(6-Chloro-2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-N-(2,3-difluoro-benzoyl)-2,3-difluoro-benzamide;-   2-Methyl-N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   3-Methyl-N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-isonicotinamide;-   2-Methyl-3-fluoro-N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   3-Cyano-N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   2-Nitro-N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   2,6-Difluoro-3-iodo-N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   2-Chloro-N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide;-   N-[4-(7-methoxy-5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-cyclohexanecarboxylic    acid amide;-   2-Methyl-N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide;-   3-Fluoro-N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-isonicotinamide;-   2-Methyl-3-fluoro-N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide;-   3-Cyano-N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide;-   3-Nitro-N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide;-   2,6-Difluoro-3-iodo-N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide;-   2-Chloro-N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide;-   N-[4-(7-methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-cyclohexanecarboxylic    acid amide;-   2-Methyl-N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide,-   2-Fluoro-N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-isonicotinamide;-   2-Methyl-3-fluoro-N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   3-Cyano-N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-Nitro-N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2,6-Difluoro-3-iodo-N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   2-Chloro-N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide;-   N-[4-(5-methoxy-benzoimidazol-1-yl)-phenyl]-cyclohexanecarboxylic    acid amide;-   (2,6-Difluoro-benzyl)-[4-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yol)-phenyl]-amine;    and

pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof.

Particular compounds of any one of formulas (I) through (XVII) includethose embodiments below.

In one embodiment, ring A is an optionally substituted phenyl.

In another embodiment, ring A is an optionally substituted pyridyl.

In another embodiment, ring A is an optionally substituted thienyl.

In another embodiment, ring A is an optionally substituted furanyl.

In another embodiment, ring A is an optionally substituted pyrrolyl.

In one embodiment, A is —CH═CH—, —CH═N—, or —N═CH—.

In another embodiment, A is —NH—, —O—, or

In one embodiment, L is a linker selected from the group consisting of—C(O)—, —NR—C(O)—, —C(O)—NR—, C(S)—, —NR—C(S)—, —C(S)—NR— (e.g.,—NH—C(O)— or —C(O)—NH—).

In another embodiment, L is —NHC(O)— or —NHCH₂—.

In another embodiment, L is —NHC(O)—, —NHC(S)NH—, —NHC(O)NH—,—CH═C(CN)—, or —NHS(O)₂—.

In one embodiment, Y is an optionally substituted 5 or 6 membered aryl,an optionally substituted 5 or 6 membered heteroaryl, or an optionallysubstituted. 5 or 6 membered cycloalkyl.

In another embodiment, Y is selected from the group consisting of analkyl, an optionally substituted alkenyl, an optionally substitutedphenyl, an optionally substituted pyridyl, an optionally substitutedfuranyl, an optionally substituted thienyl, an optionally substitutedcyclopentyl, an optionally substituted cyclohexyl, an optionallysubstituted naphthyl, an optionally substituted benzo[1,3]dioxolyl, andan optionally substituted [1,2,3]thiadiazolyl.

In another embodiment, Y is an optionally substituted phenyl or anoptionally substituted [1,2,3]thiadiazolyl.

In another embodiment, Y is an optionally substituted phenyl, anoptionally substituted pyridyl, an optionally substituted thiophenyl,[1,2,3]thiadiazolyl, an optionally substituted furanyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted naphthyl, anoptionally substituted cyclopentyl, an optionally substitutedcyclohexyl, or isobutyl.

In another embodiment, Y is an optionally substituted phenyl, anoptionally substituted pyridyl, an optionally substituted cyclopentyl,an optionally substituted cyclohexyl, or isobutyl.

In another embodiment, Y is cyclopentyl, cyclohexyl, isobutyl, propyl,t-butyl, or 2,2-dimethylpropyl.

In another embodiment, Y is an optionally substituted cycloalkyl.

In another embodiment, Y is optionally substituted aryl or optionallysubstituted heteroaryl (e.g., phenyl, pyridyl, thiophenyl,[1,2,3]thiadiazolyl, furanyl, benzo[1,3]dioxolyl, or naphthyl), any ofwhich may be optionally substituted with 1-3 (e.g., 1-2) substituentsindependently selected from halo (e.g., F, Cl, Br, and I), lower alkyl(e.g., methyl and ethyl), lower haloalkyl (e.g., CF₃), nitro, lowerhaloalkoxy, amino, phenyl, cyano, or lower alkoxy.

In another embodiment, Y is a phenyl which is optionally substitutedwith 1 to 5 substituents which are independently selected from the groupconsisting of a halo, lower alkyl, a lower haloalkyl, a lowerhaloalkoxy, cyano, or nitro.

In another embodiment, Y is an optionally substituted aryl. For exampleY is selected from the group consisting of:

In another embodiment, Y is an optionally substituted pyridyl. Forexample Y is selected from the group consisting of:

in another embodiment, Y is an optionally substituted 5-memberedheteroaryl. For example Y is selected from the group consisting of:

In a preferred embodiment, Y is selected from:

In one embodiment, Y₁ is an optionally substituted alkyl selected fromthe group consisting of propyl, 1-ethyl-pentyl, hexyl, isobutyl,phenylsulfanylmethyl, and O-ethyl-2-carboxyethyl, benzyloxymethyl.

In another embodiment, Y₁ is p-methoxybenzyl, benzyl, orm,p-dimethoxybenzyl.

In one embodiment, X is a benzoimidazolyl, a5,6,7,8-tetrahydroindolizinyl, an imidazo[4,5-a]pyridyl, animidazo[1,2-a]pyridyl, an imidazo[4,5-b]pyridyl, or animidazo[4,5-c]pyridyl, each of which may be optionally substituted withone to four substituents selected from the group consisting of loweralkoxy, lower haloalkyl, lower haloalkoxy, cyano, halo, amino, hydroxyl,lower alkylsulfanyl, lower alkylsulfinyl, lower alkysulfonyl,5-t-butyloxazolyl, —NHC(O)-(lower alkyl), —C(O)NH₂, —C(O)NH-(loweralkyl), —C(O)O-(lower alkyl), —C(O)OH, and —OC(O)-(lower alkyl).

In another embodiment, X is an optionally substituted benzoimidazolyl.For example, X is selected from the group consisting of

In another embodiment, X is an optionally substituted5,6,7,8-tetrahydroindolizinyl. For example, X is selected from the groupconsisting of:

In another embodiment, X is an optionally substituted imidazopyridyl,such as an optionally substituted imidazo[1,2-a]pyridyl (e.g.,2-trifluoromethyl-imidazo[1,2-a]pyrid-3-yl), or an optionallysubstituted imidazo[4,5-b]pyridyl (e.g.,2-trifluoromethyl-imidazo[4,5-b]pyrid-3-yl), or an optionallysubstituted imidazo[4,5-c]pyridyl (e.g.,2-trifluoromethyl-imidazo[4,5-c]pyrid-1-yl).

In one embodiment, Z is independently selected from the group consistingof a lower alkyl (e.g., CH₃), a lower haloalkyl (e.g., CF₃), cyano, andhalo (e.g., F and Cl).

In one embodiment, n is 0 and Z is absent.

In another embodiment, n is one.

In one embodiment, R, for each occurrence, is independently selectedfrom —H, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl (e.g., —H).

In one embodiment, R₆, for each occurrence, is, independently, selectedfrom the group consisting of lower alkoxy, lower haloalkoxy, cyano,—NH₂, lower alkyl, —OH, lower haloalkyl, —S(O)₂-(lower alkyl),—NHC(O)-(lower alkyl), —C(O)O-(lower alkyl), —C(O)NH₂, and —C(O)-(loweralkyl).

In another embodiment, R₆ is —OCH₃, —CF₃, —C(O)OCH₃, —OH, —OCH(CH₃)₂,—C(O)NH₂, —OC(O)CH₃, —C(O)CH₃, or —NH₂.

In one embodiment, R₇ is selected from the group consisting of halo,lower haloalkyl, lower haloalkoxy, —S-(lower alkyl), and —S(O)-(loweralkyl).

In another embodiment, R₇ is —CF₃, —OCHF₂, —SCH₃, —Cl, or —Br.

In one embodiment, R₈, for each occurrence, is, independently, selectedfrom the group consisting of halo, lower alkyl, nitro, —NH₂,—NHC(O)OC(CH₃)₃, phenyl, cyano, lower haloalkyl, and —OCH₃.

In another embodiment, R₈, for each occurrence, is, independently, ahalo, cyano or nitro.

Listed above are embodiments for substituents for the compoundsrepresented by formulas (I) through (XVII). The substituents used forcompounds of formulas (I) through (XVII) or any of the specific compoundshown in Table 1 can be used in any combination that results in theformation of a stable compound. All such combinations are expresslyencompassed in this invention.

In another embodiment, the invention relates to pharmaceuticalcompositions that comprise a compound of any one of formulas (I) through(XVII), or a compound shown in Table 1 or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, as an active ingredient,and a pharmaceutically acceptable carrier or vehicle. The compositionsare useful for immunosuppression or to treat or prevent inflammatoryconditions, allergic disorders, and immune disorders.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,allergic disorders, or immune disorders in a patient in need thereofcomprising administering an effective amount of a compound representedby any one of formulas (I) through (XVII), or a compound shown in Table1 or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates to methods forimmunosuppression or for treating or preventing inflammatory conditions,allergic disorders, or immune disorders in a patient in need thereofcomprising administering an effective amount of a pharmaceuticalcomposition that comprises a compound represented by any one of formulas(I) through (XVII), or a compound shown in Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of any one of formulas (I) through(XVII), or a compound shown in Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, are particularly usefulinhibiting immune cell (e.g., T-cells, B-cells and/or mast cells)activation (e.g., activation in response to an antigen) and/or T cell, Bcell and/or mast cell proliferation. Indicators of immune cellactivation include secretion of IL-2 by T cells, proliferation of Tcells, B cells, and/or mast cells and the like. In one embodiment, acompound of any one of formulas (I) through (XVII), or a compound shownin Table 1, inhibits immune cell activation and/or T cell, B cell and/ormast cell proliferation in a mammal (e.g., a human).

In another embodiment, compounds of any one of formula (I) through(XVII), or a compound shown in Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, can inhibit the productionof certain cytokines that regulate immune cell activation. For example,compounds of any one of formulas (I) through (XVII), or a compound shownin Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, can inhibit the production of IL-2, IL-4, IL-5,IL-13, GM-CSF, IFN-γ, TNF-α and combinations thereof. In one embodiment,compounds of any one of formulas (I) through (XVII), or a compound shownin Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, inhibit the production of IL-2. In one embodiment, acompound of any one of formulas (I) through (XVII), or a compound shownin Table 1, inhibits cytokine production in a mammal (e.g., a human).

In another embodiment, compounds of any one of formulas (I) through(XVII), or a compound shown in Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, can modulate the activityof one or more ion channel involved in activation of immune cells, suchas CRAC ion channel, TRPM4 and Kv1.3. In one embodiment, a compound ofany one of formulas (I) through (XVII), or a compound shown in Table 1,or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, can inhibit the influx of calcium ions into an immune cell(e.g., T cells, B cells, and/or mast cells) by inhibiting the action ofCRAC ion channels. In general, a decrease in I_(CRAC) current uponcontacting a cell with a compound is one indicator that the compoundinhibitions CRAC ion channels. I_(CRAC) current can be measured, forexample, using a patch clamp technique, which is described in moredetail in the examples below. In another embodiment, a compound of anyone of formulas (I) through (XVII), or a compound shown in Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, activates TRPM4 ion channels. In another embodiment, a compoundof any one of formulas (I) through (XVII), or a compound shown in Table1, or a pharmaceutically, acceptable salt, solvate, clathrate, orprodrug thereof, inhibits Kv1.3 ion channels. In one embodiment, acompound of any one of formulas (I) through (XVII), or a compound shownin Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, modulates an ion channel in a mammal (e.g., ahuman).

Exemplary Compounds of the Invention

Exemplary compounds of the invention are depicted in Table 1 below.

Compound No. Structure Chemical Name  1

2,3,6-Trifluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide  2

2,3,5-Trifluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide  3

2,3,4-Trifluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide  4

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide  5

3-Methyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- isonicotinamide  6

3-Fluoro-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-isonicotinamide  7

2,4-Dichloro-5-fluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide  8

2,3-Difluoro-N-[4-(2- trifluoromethyl-5,6,7,8-tetrahydroindolizin-3-yl)- phenyl]-benzamide  9

2,4-Difluoro-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 10

3-Nitro-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 11

2,3-Difluoro-N-[4-(2- methylsulfanyl-benzoimidazol-1-yl)-phenyl]-benzamide 12

2,3-Difluoro-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-thiobenzamide 13

2,3-Dichloro-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 14

2,3-Difluoro-N-[4-(2- trifluoromethyl-6-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 15

2-Fluoro-2-chloro-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 16

2,3,6-Trifluoro-5-amino-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 17

2,3-Difluoro-N-[3-methyl-4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 18

2-Methyl-N-[4-(2- trifluoromethyl-5,6,7,8- tetrahydroindolizin-3-yl)-phenyl]-benzamide 19

2,3-Difluoro-N-[4-(2- trifluoromethyl-5,6,7,8-tetrahydroindolizin-3-yl)- phenyl]-benzamide 20

2,3-Difluoro-N-[4-(2- trifluoromethyl-6-cyano-benzoimidazol-1-yl)-phenyl]- benzamide 21

2,3-Difluoro-N-[4-(2- trifluoromethyl-4-amino-benzoimidazol-1-yl)-phenyl]- benzamide 22

N-(3-{N-[4-(2-trifluoromethyl- benzoimidazol-1-yl)-phenyl]-carbamoyl}-2,4,5-trifluoro- phenyl)-carbamic acid t-butyl ester 23

2,3-Difluoro-N-[4-(2-chloro- benzoimidazol-1-yl)-phenyl]- benzamide 24

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid {N-[4-(2-chloro-5,6,7,8-tetrahydroindolizin-3-yl)- phenyl]} amide 25

2,3-Difluoro-N-[2-chloro-4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 26

2,5-Difluoro-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 27

3-Fluoro-N-[4-(2-trifluoromethyl- benzoimidazol-1-yl)-phenyl]-isonicotinamide 28

2,3-Difluoro-N-[4-(2-bromo- benzoimidazol-1-yl)-phenyl]- benzamide 29

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid {N-[4-(2-trifluoromethyl-benzoimidazol- 1-yl)-phenyl]} amide 30

2,3-Difluoro-N-[3- trifluoromethyl-4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 31

N-(4-{N-[4-(2-trifluoromethyl- benzoimidazol-1-yl)-phenyl]-carbamoyl}-2,3-difluoro- phenyl)-carbamic acid t-butyl ester 32

2,3-Difluoro-N-[4-(2- trifluoromethyl-5,6-dimethoxy-benzoimidazol-1-yl)-phenyl]- benzamide 33

2,3-Difluoro-N-[4-(2-iodo- benzoimidazol-1-yl)-phenyl]- benzamide 34

N′-[2-(2-trifluoromethyl- benzoimidazol-1-yl)-pyrid-5-yl]-N-(2,5-difluoro-phenyl)-thiourea 35

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-tert-butyl-benzoimidazol-1-yl)-phenyl]- benzamide 36

2,3-Difluoro-N-[2-(2- trifluoromethyl-benzoimidazol-1-yl)-pyrid-3-yl]-benzamide 37

2,3-Difluoro-N-[3-cyano-4-(2- trifluoromethyl-benzoimidiazol-1-yl)-phenyl]-benzamide 38

2,5-Difluoro-N-[3-chloro-4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 39

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-amino-benzoimidazol-1-yl)-phenyl]- benzamide 40

2,3-Difluoro-N-[4-(2- methanesulfinyl-benzoimidazol-1-yl)-phenyl]-benzamide 41

2,5-Difluoro-N-[2-(2- trifluoromethyl-benzoimidazol-1-yl)-pyrid-5-yl]-benzamide 42

2,3-Difluoro-N-[4-(2- trifluoromethyl-5,6-dimethyl-benzoimidazol-1-yl)-phenyl]- benzamide 43

2,3-Difluoro-4-amino-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 44

2,3-Difluoro-N-[4-(2- trifluoromethyl-imidazo[4,5-b]pyrid-3-yl)-phenyl]-benzamide 45

N-[4-(2-trifluoromethyl- benzoimidazol-1-yl)-phenyl]- nicotinamide 46

N-(2,3-difluorophenyl)-4-(2- trifluoromethyl-benzoimidazol-1-yl)-benzamide 47

1-(2,3-difluoro-phenyl)-3-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-acrylonitrile 48

1-(2,5-difluoro-phenyl)-3-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-acrylonitrile 49

2,3-Difluoro-N-[4-(2-isopropyl- benzoimidazol-1-yl)-phenyl]- benzamide50

N′-[4-(2-trifluoromethy- benzoimidazol-1-yl)-phenyl]-N-(2,5-difluoropheyl)-urea 51

1-Oxo-3-fluoro-N-[4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-isonicotinamide 52

2,3-Difluoro-N-[4- (trifluoromethyl-benzoimidazol- 1-yl)-phenyl]-benzenesulfonamide 53

2,3-Difluoro-N-[3-acetylamino- 4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]- benzamide 54

2,3-Difluoro-N-[4- (benzoimidazol-1-yl)-phenyl]- benzamide 55

2,3-Difluoro-N-[2-methyl-4-(2- trifluoromethyl-benzoimidazol-1-yl)-phenyl]-benzamide 56

2,5-Difluoro-N-[4-(2- trifluoromethyl-imidiazo[4,5-b]pyrid-3-yl)-phenyl]-benzamide 57

2,3-Difluoro-N-{4-[2- trifluoromethyl-5-(1,3-dioxo-isoindol-2-yl)-benzoimidazol-1- yl]-phenyl}-benzamide 58

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid {N-[4-(2-trifluoromethyl-imidazo[4,5- b]pyrid-3-yl)-phenyl]} amide 59

2,3-Difluoro-N-[4-(2-methyl- benzoimidazol-1-yl)-phenyl]- benzamide 60

2,3-Difluoro-N-[4-(2- trifluoromethyl-5,6-dihydroxy-benzoimidazol-1-yl)-phenyl]- benzamide 61

2,3-Difluoro-N-[4-(2- trifluoromethyl-imidazo[4,5-c]pyrid-1-yl)-phenyl]-benzamide 62

4-Methyl-[1,2,3]thiadiazole-5- carboxylic acid {N-[2-(2-trifluoromethyl-benzoimidazol- 1-yl)-pyrid-5-yl]} amide 63

2,4,6-Trichloro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 64

2,3-Difluoro-N-{4-[2,5-di- (trifluoromethyl)-benzoimidazol-1-yl]-phenyl}-benzamide 65

2,3-Difluoro-N-[4-(2- trifluoromethyl-5- methanesulfonyl-benzoimidazol-1-yl)-phenyl]- benzamide 66

4-Butyl-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 67

2,5-Difluoro-N-{4-[2- trifluoromethyl-5-(5-tert-butyl-oxazol-2-yl)-benzoimidazol-1- yl]-phenyl}-benzamide 68

2,3-Difluoro-N-{4-[2- trifluoromethyl-5-(5-tert-butyl-oxazol-2-yl)-benzoimidazol-1- yl]-phenyl}-benzamide 69

Furan-2-carboxylic acid (N-{4- [2-trifluoromethyl-5-(5-tert-butyl-oxazol-2-yl)-benzoimidazol-1- yl]-phenyl}) amide 70

2,3-Difluoro-N-[4-(2- trifluoromethyl-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide 71

2,3,4,5-Tetrafluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 72

4-Phenyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 73

4-Iodo-N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 74

Naphthalene-2-carboxylic acid {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)- phenyl]} amide 75

Benzo[1,3]dioxole-5-carboxylic acid {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)- phenyl]} amide 76

4-Methyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 77

4-Cyano-N-[4-(2- trifluoromethyl-5-methoxy- benzoimidazol-1-yl)-phenyl]-benzamide 78

4-Nitro-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 79

4-Ethyl-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 80

4-Trifluoromethyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 81

3,5-Dinitro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 82

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-butyramide 83

Naphthalene-1-carboxylic acid {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)- phenyl]} amide 84

3-Methyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- but-2-enoic acid amide 85

4-Propyl-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 86

Thiophene-2-carboxylic acid {N-[4-(2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)- phenyl]} amide 87

2-Ethyl-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-hexanoic acid amide 88

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-heptanoic acid amide 89

3-Methoxy-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 90

2-Phenyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- cyclopropanecarboxylic acid amide 91

3-Trifluoromethyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 92

2-(4-Methoxy-phenyl)-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- acetamide 93

2,3-Difluoro-N-[4-(2- trifluoromethyl-6-acetylamino-benzoimidazol-1-yl)-phenyl]- benzamide 94

2-(Thien-2-yl)-N-[4-(2 trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- acetamide 95

2-phenyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- acetamide 96

2-Trifluoromethyl-1-[4-(2,3- difluoro-benzoylamimo)-phenyl]-1H-benzoimidazole-5- carboxylic acid methyl ester 97

2,3,4,5,6-Pentafluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 98

2,4-Difluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 99

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-hydroxy-benzoimidazol-1-yl)-phenyl]- benzamide 100 

2,5-Difluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 101 

3-Cyano-N-[4-(2- trifluoromethyl-5-methoxy- benzoimidazol-1-yl)-phenyl]-benzamide 102 

2,6-Dichloro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 103 

3,5-Dichloro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 104 

2-Bromo-N-[4-(2- trifluoromethyl-5-methoxy- benzoimidazol-1-yl)-phenyl]-benzamide 105 

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-cyclopentanecarboxylic acid amide 106 

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-cyclohexanecarboxylic acid amide 107 

2-Nitro-N-[4-(2-trifluoromethyl- 5-methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 108 

4-Chloro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 109 

3-Chloro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 110 

3,4-Difluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 111 

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 112 

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-isopropoxy-benzoimidazol-1-yl)-phenyl]- benzamide 113 

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-carbamoyl-benzoimidazol-1-yl)-phenyl]- benzamide 114 

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-isonicotinamide 115 

2-Iodo-N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 116 

3-Methyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- butyramide 117 

3,5-Dichloro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 118 

3-Bromo-N-[4-(2- trifluoromethyl-5-methoxy- benzoimidazol-1-yl)-phenyl]-benzamide 119 

4-Bromo-N-[4-(2- trifluoromethyl-5-methoxy- benzoimidazol-1-yl)-phenyl]-benzamide 120 

Furan-2-carboxylic acid {N-[4- (2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]}- amide 121 

1-(2,2,2-Trifluoroacetyl)-N-[4- (2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- pyrrolidine-2-carboxylic acid amide 122 

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-acrylamide 123 

2-Benzyloxy-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- acetamide 124 

2-Phenylsulfanyl-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- acetamide 125 

N-[4-(2-trifluoromethyl-5- methoxy-benzoimidazol-1-yl)-phenyl]-succinamic acid ethyl ester 126 

2-Chloro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 127 

2,5-Di-(trifluoromethyl)-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 128 

2-Methoxy-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 129 

3,5-Di-(trifluoromethyl)-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 130 

2,5-Dimethoxy-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzamide 131 

2-(3,4-dimethoxy-phenyl)-N-[4- (2-trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- acetamide 132 

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-acetoxy-benzoimidazol-1-yl)-phenyl]- benzamide 133 

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-acetyl-benzoimidazol-1-yl)-phenyl]- benzamide 134 

2,3-Difluoro-N-[4-(2- trifluoromethyl-5-amino-benzoimidazol-1-yl)-phenyl]- benzamide 135 

2,6-Difluoro-N-[4-(2- trifluoromethyl-5-methoxy-benzoimidazol-1-yl)-phenyl]- benzylamine, HCl salt 136 

Isomeric mixture of N-[4-(5- Chloro-2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-N- (2,3-difluoro-benzoyl)-2,3-difluoro-benzamide & N-[4-(6- Chloro-2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-N- (2,3-difluoro-benzoyl)-2,3-difluoro-benzamide

137 

2-Methyl-N-[4-(7-methoxy- 5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide 138 

3-Methyl-N-[4-(7-methoxy- 5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-isonicotinamide 139 

2-Methyl-3-fluoro-N-[4-(7- methoxy-5,6,7,8- tetrahydroindolizin-3-yl)-phenyl]-benzamide 140 

3-Cyano-N-[4-(7-methoxy- 5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide 141 

2-Nitro-N-[4-(7-methoxy- 5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide 142 

2,6-Difluoro-3-iodo-N-[4-(7- methoxy-5,6,7,8- tetrahydroindolizin-3-yl)-phenyl]-benzamide 143 

2-Chloro-N-[4-(7-methoxy- 5,6,7,8-tetrahydroindolizin-3-yl)-phenyl]-benzamide 144 

N-[4-(7-methoxy-5,6,7,8- tetrahydroindolizin-3-yl)-phenyl]-cyclohexanecarboxylic acid amide 145 

2-Methyl-N-[4-(7-methoxy- imidazo[1,2-a]pyrid-3-yl)- phenyl]-benzamide146 

3-Fluoro-N-[4-(7-methoxy- imidazo[1,2-a]pyrid-3-yl)-phenyl]-isonicotinamide 147 

2-Methyl-3-fluoro-N-[4-(7- methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide 148 

3-Cyano-N-[4-(7-methoxy- imidazo[1,2-a]pyrid-3-yl)- phenyl]-benzamide149 

3-Nitro-N-[4-(7-methoxy- imidazo[1,2-a]pyrid-3-yl)- phenyl]-benzamide150 

2,6-Difluoro-3-iodo-N-[4-(7- methoxy-imidazo[1,2-a]pyrid-3-yl)-phenyl]-benzamide 151 

2-Chloro-N-[4-(7-methoxy- imidazo[1,2-a]pyrid-3-yl)- phenyl]-benzamide152 

N-[4-(7-methoxy-imidazo[1,2- a]pyrid-3-yl)-phenyl]-cyclohexanecarboxylic acid amide 153 

2-Methyl-N-[4-(5-methoxy- benzoimidazol-1-yl)-phenyl]- benzamide 154 

2-Fluoro-N-[4-(5-methoxy- benzoimidazol-1-yl)-phenyl]- isonicotinamide156 

2-Methyl-3-fluoro-N-[4-(5- methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 157 

3-Cyano-N-[4-(5-methoxy- benzoimidazol-1-yl)-phenyl]- benzamide 158 

2-Nitro-N-[4-(5-methoxy- benzoimidazol-1-yl)-phenyl]- benzamide 159 

2,6-Difluoro-3-iodo-N-[4-(5- methoxy-benzoimidazol-1-yl)-phenyl]-benzamide 160 

2-Chloro-N-[4-(5-methoxy- benzoimidazol-1-yl)-phenyl]- benzamide 161 

N-[4-(5-methoxy- benzoimidazol-1-yl)-phenyl]- cyclohexanecarboxylic acidamide 187 

(2,6-Difluoro-benzyl)-[4-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yol)-phenyl]- amine 188 

(2,6-Difluoro-benzyl)-[4-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yol)-phenyl]- amine, benzenesulfonic acid salt 189 

(2,6-Difluoro-benzyl)-[4-(5- methoxy-2-trifluoromethyl-benzoimidazol-1-yol)-phenyl]- amine, sulfuric acid salt

Mechanism of Action

Activation of 1-lymphocytes in response to an antigen is dependent oncalcium ion oscillations. Calcium ion oscillations in T-lymphocytes aretriggered through stimulation of the T-cell antigen receptor, andinvolve calcium ion influx through the stored-operatedCa²⁺-release-activated Ca²⁺ (CRAG) channel. Although the molecularstructure of the CRAC ion channel has not been identified, a detailedelectrophysiological profile of the channel exist. Thus, inhibition ofCRAC ion channels can be measured by measuring inhibition of theI_(CRAC) current. Calcium ion oscillations in T-cells have beenimplicated in the activation of several transcription factors (e.g.,NEAT, Oct/Oap and NFκB) which are critical for T-cell activation (Lewis,Biochemical Society Transactions (2003), 31:925-929, the entireteachings of which are incorporated herein by reference). Certaincompounds of any one of formulas (I) through (XVII), or compounds shownin Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, inhibit the activity of CRAG ion channels. Withoutwishing to be bound by any theory, it is believed that the compounds ofthe invention inhibit immune cell activation by inhibiting the activityof CRAC ion channels.

Compounds of any one of formulas (I) through (XVII), or compounds shownin Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, activate transient receptor potential melastatin 4(TRPM4) ion channels. TRPM4 ion channels have been shown to modulate themembrane potential of the cell and, when activated, depolarize the cellmembrane, thereby inhibiting calcium entry through other calciumpermeable pathways (see Launay et al., Cell (2002), 109:397-407, theentire teachings of which are incorporated herein by reference).Therefore, it has been suggested that activation of the TRPM4 channelsinhibits T-cell activation by inhibiting the activation of transcriptionfactors that are dependent on calcium ion signalling.

Compounds of any one of formulas (I) through (XVII), or compounds shownin Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, inhibit the activity of Kv1.3 potassium ionchannels. Kv1.3 is another ion channel which is involved in control ofmembrane potential and calcium influx. Blockade of Kv1.3 has been shownto prevent T-cell activation and attenuate immune responses in vivo (Kooet al., Cellular Immunology (1999), 197:99-107, the entire teachings ofwhich are incorporated herein by reference).

Methods of Treatment and Prevention

In accordance with the invention, an effective amount of a compound ofany one of formulas (I) through (XVII), or a compound shown in Table 1,or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, or a pharmaceutical composition comprising a compound of anyone of formulas (I) through (XVII), or a compound shown in Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, is administered to a patient in need of immunosuppression or inneed of treatment or prevention of an inflammatory condition or immunedisorder. Such patients may be treatment naïve or may experience partialor no response to conventional therapies.

Responsiveness of a particular inflammatory condition or immune disorderin a subject can be measured directly (e.g., measuring blood levels ofinflammatory cytokines (such as IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α,IFN-γ and the like) after administration of a compound or formulation ofthis invention), or can be inferred based on an understanding of diseaseetiology and progression. A compound of any one of formulas (I) through(XVII), or a compound shown in Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, can be assayed in vitro orin vivo, for the desired therapeutic or prophylactic activity, prior touse in humans. For example, known animal models of inflammatoryconditions or immune disorders can be used to demonstrate the safety andefficacy of compounds of this invention.

Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions and dosage forms of the invention compriseone or more active ingredients in relative amounts and formulated insuch a way that a given pharmaceutical composition or dosage form can beused for immunosuppression or to treat or prevent inflammatoryconditions and immune disorders. Preferred pharmaceutical compositionsand dosage forms comprise a compound of any one of formulas (I) through(XVII), or a compound shown in Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, optionally in combinationwith one or more additional active agents.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration, to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, this inventionencompasses pharmaceutical compositions and dosage forms that containlittle, if any, lactose. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmacopeia (USP) SP(XXI)/NF (XVI). In general, lactose-freecompositions comprise active ingredients, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Preferred lactose-free dosage forms comprise activeingredients, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise acompound of any one of formulas (I) through (XVII), or a compound shownin Table 1, or a pharmaceutically acceptable salt, solvate, clathrate,or prodrug thereof, in an amount of from about 1 mg to about 1000 mg,preferably in an amount of from about 50 mg to about 500 mg, and mostpreferably in an amount of from about 75 mg to about 350 mg. The typicaltotal daily dosage of a compound of any one of formulas (I) through(XVII), or a compound shown in Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, can range from about 1 mgto about 5000 mg per day, preferably in an amount from about 50 mg toabout 1500 mg per day, more preferably from about 75 mg to about 1000 mgper day. It is within the skill of the art to determine the appropriatedose and dosage form for a given patient.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic add; calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention, include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydroxypropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients of the invention. Theinvention thus encompasses single unit dosage forms suitable for oraladministration such as, but not limited to, tablets, capsules, gelcaps,and caplets that are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-release,formulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, in spheroids which further comprisemicrocrystalline cellulose and, optionally,hydroxypropylmethyl-cellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Such extended release formulations canbe prepared according to U.S. Pat. No. 6,274,171, the entirely of whichis incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of any one of formulas (I) through(XVII), or a compound shown in Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof, by weight, about 50% toabout 94% microcrystalline cellulose, NF, by weight, and optionally fromabout 0.25% to about 1% by weight of hydroxypropyl-methylcellulose, USP,wherein the spheroids are coated with a film coating compositioncomprised of ethyl cellulose and hydroxypropylmethylcellulose.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are, not limited, to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection, RingersInjection, Dextrose Injection, Dextrose and Sodium Chloride Injection,and Lactated Ringer's Injection; water-miscible vehicles such as, butnot limited to, ethyl alcohol, polyethylene glycol, and polypropyleneglycol; and non-aqueous vehicles such as, but not limited to, corn oil,cottonseed, oil, peanut oil, sesame oil, ethyl oleate, isopropylmyristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can, be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span. 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Combination Therapy

The methods for immunosuppression or for treating or preventinginflammatory conditions and immune disorders in a patient in needthereof can further comprise administering to the patient beingadministered a compound of this invention, an effective amount of one ormore other active agents. Such active agents may include those usedconventionally for immunosuppression or for inflammatory conditions orimmune disorders. These other active agents may also be those thatprovide other benefits when administered in combination with thecompounds of this invention. For example, other therapeutic agents mayinclude, without limitation, steroids, non-steroidal anti-inflammatoryagents, antihistamines, analgesics, immunosuppressive agents andsuitable mixtures thereof. In such combination therapy treatment, boththe compounds of this invention and the other drug agent(s) areadministered to a subject (e.g., humans, male or female) by conventionalmethods. The agents may be administered in a single dosage form or inseparate dosage forms. Effective amounts of the other therapeutic agentsand dosage forms are well known to those skilled in the art. It is wellwithin the skilled artisan's purview to determine the other therapeuticagents optimal effective-amount range.

In one embodiment of the invention where another therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount when the other therapeuticagent is not administered. In another embodiment, the effective amountof the conventional agent is less than its effective amount when thecompound of this invention is not administered. In this way; undesiredside effects associated with high doses of either agent may beminimized. Other potential advantages (including without limitationimproved dosing regimens and/or reduced drug cost) will be apparent tothose of skill in the art.

In one embodiment relating to autoimmune and inflammatory conditions,the other therapeutic agent may be a steroid or a non-steroidalanti-inflammatory agent. Particularly useful non-steroidalanti-inflammatory agents, include, but are not limited to, aspirin,ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fiuprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam, isoxicam; salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone and pharmaceutically acceptablesalts thereof and mixtures thereof. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

Of particular relevance to allergic disorders, the other therapeuticagent may be an antihistamine. Useful antihistamines include, but arenot limited to, loratidine, cetirizine, fexofenadine, desloratidine,diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine,promethazine, terfenadine, doxepin, carbinoxamine, clemastine,tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine,cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine,and mixtures thereof. For a more detailed description of antihistamines,see Goodman & Gilman's The Pharmacological Basis of Therapeutics (2001)651-57, 10^(th) ed).

Immunosuppressive agents include glucocorticoids, corticosteroids (suchas Prednisone or Solumedrol), T cell blockers (such as cyclosporin A andFK506), purine analogs (such as azathioprine (Imuran)), pyrimidineanalogs (such as cytosine arabinoside), alkylating agents (such asnitrogen mustard, phenylalanine mustard, buslfan, and cyclophosphamide),folic acid antagonists (such as aminopterin and methotrexate),antibiotics (such as rapamycin, actinomycin D, mitomycin C, puramycin,and chloramphenicol), human IgG, antilymphocyte globulin (ALG), andantibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5,anti-CD7, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1,anti-CD20 (Rituxan), anti-IL-12 and antibodies to immunotoxins).

The foregoing and other useful combination therapies will be understoodand appreciated by those of skill in the art. Potential advantages ofsuch combination therapies include, a different efficacy profile, theability to use less of each of the individual active ingredients tominimize toxic side effects, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Other Embodiments

The compounds of this invention may be used as research tools (forexample, as a positive control for evaluating other potential TRPM4activators, CRAG or Kv1.3 inhibitors, or IL-2, IL-4, IL-5, IL-13,GM-CSF, TNF-α, and/or INF-γ inhibitors). These and other uses andembodiments of the compounds and compositions of this invention will beapparent to those of ordinary skill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES Experimental Rationale

Without wishing to be bound by theory, it is believed that the compoundsof this invention activate TRPM4, and/or inhibit Kv1.3 and CRAC ionchannels thereby inhibiting production of IL-2 and other key cytokinesinvolved with inflammatory and immune responses. The examples thatfollow demonstrate these properties.

Materials and General Methods

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Human leukemic T cells (Jurkat cells) and HEK 293 cells transfected withthe FLAG-humanTRPM4/pcDNA4/TO construct were grown on glass coverslipswith DMEM medium supplemented with 10% FBS, blasticidin (5 μg/mL) andzeocin (0.4 g/mL). TRPM4 expression was induced one day before use byadding 1 μg/mL tetracycline to the culture medium and patch clampexperiments were performed 16-24 hours post-induction (for additionaldetails see Launay et al. (2000)).

Patch clamp experiments were performed in the tight-seal whole-cellconfiguration at 21-25° C. High resolution current recordings wereacquired by a computer-based patch clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Patch pipettes had resistances between 2-4 MΩ afterfilling with the standard intracellular solution. Immediately followingestablishment of the whole-cell configuration, voltage ramps of 50-200ms duration spanning the voltage range of −100 to +100 mV were deliveredat a rate of 0.5 Hz over a period of. 300-400 seconds. All voltages werecorrected from a liquid junction potential of 10 mV between external andinternal solutions when using glutamate as the intracellular anion.Currents were filtered at 2.9 kHz and digitized at 10 Ωs intervals.Capacitive currents and series resistance were determined and correctedbefore each voltage ramp using the automatic capacitance compensation ofthe EPC-9. The low resolution temporal development of membrane currentswas assessed by extracting the current amplitude at −80 mV or +80 mVfrom individual ramp current records.

Example 1 Synthesis of Representative Exemplary Compounds of thisInvention

A. General Synthesis of Compounds in which X is a Benzoimidazolyl(Method 1)

A suspension of a substituted benzoimidazole (27 mmol) and potassiumt-butoxide (3.6 g, 30 mmol) in DMF (50 mL) was stirred at rt for 30 min.1-Fluoro-4-nitro-benzene (4.2 g, 30 mmol) was added and the reactionmixture was heated to 150° C. for 4 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate (EtOAc). The organic extractwas washed with water and dried. The oil obtained, on concentration wasflash chromatographed on silica gel to give 162 in 10-90% yields.

A stirred suspension of compound 162 (12 mmol) in EtOAc (100 mL) and 10%Pd—C (150 mg) was attached to a H₂ balloon for 4-12 h. The mixture wasfiltered through celite and concentrated to give compound 163.

To a mixture of compound 163 (4.0 mmol) and pyridine (1.3 mL) inchloroform (50 mL) at room temperature was added an acid chloride (5.0mmol). The reaction mixture was stirred for 2-12 h. The reaction mixturewas diluted with 1N HCl, extracted with chloroform and dried. Theresidue obtained on concentration was crystallized from EtOAc/hexane orflash chromatographed to give the product 164 in 30%-95% yields.

B. General Synthesis of Compounds in which X is a Benzoimidazolyl(Method 2)

A suspension of (optionally substituted)-1-chloro-2-nitro-benzene (60mmol), (optionally substituted)-benzene-1,4-diamine (33 g, 0.30 mol) andpotassium carbonate (25 g, 0.30 mol) in DMF (200 mL) was heated at 120°C. for 4-120 hours. The reaction mixture was diluted with water andextracted with EtOAc. The organic extract was washed with water anddried. The oil obtained on concentration was flash chromatographed onsilica gel to give compound 165 in 10-90% yields.

A stirred suspension of compound 165 (15 mmol) in EtOAc (100 mL) and 10%Pd—C (150 mg) was hydrogenated at room temperature for 4-12 h. Themixture was filtered through celite and concentrated (step 1). The oilobtained was mixed with trifluoroacetic acid (5 mL) and trifluoroaceticanhydride (5 mL) and heated at 80° C. for 30 min. The mixture wasdiluted with water, neutralized with sodium bicarbonate, and extractedwith EtOAc. The organic extract was dried and concentrated (step 2). Theoil obtained was diluted with methanol (100 mL), potassium carbonate(2.5 g, 30 mmol) was added, and the mixture was refluxed for 24 h. Thereaction mixture was diluted with water and extracted with EtOAc. Theorganic extract was washed and dried (step 3). Removal of solvent gavecompound 1.66 in 20-95% yields.

To a mixture of compound 166 (0.1.6 mmol) and pyridine (0.1 mL) inchloroform (5 mL) at room-temperature was added an acyl chloride (0.25mmol), and the reaction was stirred for 2 h. The reaction mixture wasdiluted with 1N HCl, extracted with chloroform and dried. The residueobtained on concentration was crystallized from EtOAc/hexane to give theproduct 167 in 30%-95% yields.

C. General Synthesis of Compounds in which X is a Benzoimidazolyl(Method 3)

To a stirred solution of benzimidazole 168 (6.00 mmols) andp-fluoronitrobenzene 169 (6.00 mmols) in 10 mL of anhydrous DMF, wasadded [potassium t-butoxide (t-BuOK) (7.61 mmols, 1.25 eq.), and thereaction mixture was stirred at 80° C. overnight. The reaction mixturewas added into 50 mL of water and the product was extracted with ethylacetate (3×20 mL). The extracts were washed with brine and concentrated.Column chromatography on silica gel using mixture of hexane:ethylacetate provided compound 170 in 25-45% yields.

To a stirred solution of compound 170 (1.31 mmols) in 20 mL of 1:1CH₂Cl₂:EtOH, was added SnCl₂ (13.06 mmols) followed by a few drops ofwater. The mixture was stirred overnight and concentrated. 20 mL ofwater was added to the residue, and the solution the brought to pH ˜8-9using 2N NaOH. The resulting mixture was extracted with ethyl acetate(20 mL×4), washed with brine (20 mL), dried over Na₂SO₄, andconcentrated to afforded compound 171 in 70-97% yields.

To a solution of compound 171 (0.30 mmols) in 5 mL of CH₂Cl₂, was addedan acyl chloride 172 (0.30 mmols), followed by diisopropyl-ethylamine(0.60 mmols). The resultant mixture was stirred at room temperature for30 min and eluted through a short pad of silica gel using mixture ofhexane:ethyl acetate to afford, upon concentration, the product 173 in80-96% yields.

D. Synthesis of Compounds 34 and 50

A solution of the intermediate A (see Method 1, Compound 163) (2 mmol)and 1,4-Difluoro-2-isocyanato-benzene (2 mmol) or1,4-Difluoro-2-isothiocyanato-benzene (2 mmol) in DCM (2 mL) was stirredat room temperature for 48 hours. After removal of the solvent andvolatile components, the crude material was separated by silica gelchromatography (hexane to 10% hexane/EtOAc to 50% hexane/EtOAc) toafford Compound 34 or Compound 5.

E. Synthesis of Compound 12

To a solution of Compound 9 (100 mg, 0.24 mmol) in dry benzene (10 mL)was added Lawesson's reagent (80 mg, 0.2 mmol) and the mixture washeated to reflux for 2 h. Undissolvable materials were then filtered offthrough celite, and the filtrate was concentrated followed by silica gelchromatography (hexane to 20% hexane/EtOAc) to afford Compound 12 as ayellow solid.

F. Synthesis of Compound 52

To a stirred solution of 2,3-difluoroanilline (2.58 g, 20 mmol) in water(25 mL) and concentrated hydrochloric acid (15 mL) at −10° C. was addeda solution of NaNO₂ (1.45 g, 21 mmol) in water (3 mL) dropwise over aperiod of 30 min. After 10 min, this mixture was added to a SO₂saturated solution in acetic acid (20 mL) and concentrated hydrochloricacid (2 mL) containing CuCl (0.6 g) at 0° C. The mixture was partitionedbetween water and EtOAc. Organic layer was separated and washed withNaHCO₃; dried (Na₂SO₄). The crude product 2,3-Difluoro-benzenesulfonylchloride thus obtained was used directly without further purification.

The above obtained 2,3-Difluoro-benzenesulfonyl chloride (1.2 equiv.)was added to a solution of the “intermediate A” in chloroform andpyridine and the mixture was allowed to react at room temperature for 3h. The mixture was diluted with dichloromethane (DCM) and washed withdilute hydrochloric acid and dried (Na₂SO₄). Pure product of Compound 52was obtained by silica gel chromatography (30% hexane/EtOAc) as a whitesolid.

G. Synthesis of Compounds 46 and 47

A stirred mixture of 2-Trifluoromethyl-1H-benzoimidazole (4.92 g, 26.4mmol), 4-fluorobenaldehyde (3.1 mL, 29.1 mmol), and K₂CO₃ (4.37 g, 31.7mmol) in DMF (50 mL) was heated to 150° C. for 16 h. After being cooledto room temperature, the reaction mixture was partitioned between H₂Oand EtOAC. After usual workup, the crude product was purified by silicagel chromatography (20% Hexane/EtOAc to 30% Hexane/EtOAc) to afford ayellow oil which was subjected to a second silica gel chromatography(DMC) to provide the aldehyde intermediate4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde as a white solid(4.0 g).

To a solution of the above4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.155 g, 0.53mmol) and (2,3-Difluoro-phenyl)-acetonitrile (83 mg, 0.54 mmol) in EtOH(5 mL) was added a solution of KOH (0.2 g) in H₂O (0.5 mL). The mixturewas then stirred at rt for 1 h, partitioned between EtOAc/H₂O. Theorganic layer was dried and concentrated followed by silica gelchromatography (20% Hexane/EtOAc) to afford the product Compound 47 as acolorless oil.

To a stirred solution of4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.58 g, 2 mmol)in acetone (25 mL) was added Jones's reagent (1.0 mL, 2.0 M) at 0° C.After stirring at room temperature for 2 h, the mixture was partitionedbetween EtOAc and saturated NaHCO₃ solution. After usual workup, thecrude material was separated by silica gel chromatography (50%Hexane/EtOAc to EtOAc) to afford the intermediate acid4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzoic acid as awhile solid(490 mg).

To a stirred solution of4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzoic acid (102 mg, 0.33mmol) in dry CHCl₃ (15 mL) was added oxalyl chloride (0.09 mL) followedby one drop of DMF at room temperature. After 1 h, the reaction pot wasconcentrated and Vacuum dried. Dry chloroform (15 mL) and pyridine (0.1mL) was then added followed by the addition of 2,3-difluoroanilline (36mg, 0.28 mmol). The reaction was monitored by TLC, after completion, themixture was partitioned between 1N HCl and DCM. Organic layer wasseparated and dried (Na₂SO₄). Removal of solvents followed silica gelchromatography (20% hexane/EtOAc) afforded the product Compound 46 as awhite solid.

Methods 1-3, shown above, were utilized with appropriate startingmaterials and reagents to produce the following compounds of theinvention. Choice of the appropriate starting materials and reagentswill be readily apparent to one of skill in the art for these and othercompounds of this invention.

Compound 3

¹H-NMR (CDCl₃) δ (ppm) 8.5 (br, 1H), 7.9 (m, 3H), 7.5 (d, 2H, J=8), 7.34(s, 1H), 7.2 (m, 1H), 7.0 (m, 2H), 3.88 (s, 3H); ESMS clcd forC₂₂H₁₃F₆N₃O₂: 465:1. Found: 466.1 (M+H)⁺.

Compound 6

¹H NMR δ (DMSO-d₆) 11.06 (s, 1H), 8.81 (d, J=0.9 Hz, 1H), 8.64 (dd,J₁=0.9 Hz, J₂=4.8 Hz, 1H), 7.96 (d, J=9 Hz, 2H), 7.76 (t, J=5.7 Hz, 1H),7.62 (d, J=9 Hz, 2H), 7.43 (d, J=2:4 Hz, 1H), 7.07-7.15 (m, 2H), 3.84(s, 3H); ESMS Calcd (C₂₁H₁₄F₄N₄O₂): 430.11. found (M+1) 431.11

Compound 9

¹H-NMR (CDCl3) δ (ppm), 8.50 (d, J=13.8 Hz, 1H), 7.97-7.90 (m, 4H),7.48-7.39 (m, 5H), 7.34-7.31 (m, 1H), 7.21-7.18 (m, 1H); ESMS clcd forC₂₁H₁₂F₅N₃O: 417.10. Found: 418.1 (M+H)⁺.

Compound 11

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.5 (d, J=15 Hz, 1H), 7.91-7.86 (m,3H), 7.73 (d, J=7.8 Hz, 1H), 7.49-7.44 (m, 2H), 7.42-7.35 (m, 1H),7.32-7.10 (m, 4H), 2.76 (s, 3H).

Compound 21

¹H-NMR (DMSO-d₆) δ (ppm) 10.9 (br, 1H), 8.0 (d, 2H, J=9), 7.7 (m, 1H),7.6 (m, 3H), 7.4 (m, 1H), 7.1 (m, 1H), 6.5 (d, 1H, J=9), 6.3 (d, 1H,J=9), 5.8 (br, 2H); ESMS clcd for C₂₁H₁₃F₆N₄O: 432.1. Found: 433.0(M+H)⁺.

Compound 22

¹H-NMR (CDCl₃) δ (ppm) 9.0 (br, 1H), 8.1 (m, 1H), 7.9 (m, 3H), 7.4 (m,4H), 7.2 (m, 1H), 6.7 (br, 1H), 1.56 (s, 9H); ESMS clcd forC₂₆H₂₀F₆N₄O₃: 550.1. Found: 551.1 (M+H)⁺.

Compound 27

¹H-NMR (DMSO-d₆) δ (ppm) 11.1 (br, 1H), 8.7 (s, 1H), 8.4 (m, 1H), 8.0(d, 2H, J=9), 7.8 (d, 2H, J=9), 7.7 (m, 2H), 7.5 (m, 2H), 7.3 (m, 1H);ESMS clcd for C₂₀H₁₂F₄N₄O: 400.1. Found: 401.1 (M+H)⁺.

Compound 34

¹H-NMR (CD₃OD) δ 8.9 (d, 1H), 8.3 (s, 1H), 7.85-7.95 (m, 2H), 7.71 (d,2H, J=8), 7.45 (d, 2H, J=8), 7.36-7.45 (m, 2H), 7.15-7.25 (m, 1H),7.04-7.15 (m, 1H), 6.85-6.95 (m, 1H) ppm; ESMS clcd for C₂₀H₁₂F₆N₆S:449.1. Found: 450.1 (M+H)⁺.

Compound 45

¹H-NMR (CDCl3) δ (ppm), 9.14 (d, J=2.4 Hz 1H), 8.82 (m, 1H), 8.28-8.25(m, 2H), 7.95-7.91 (m, 3H), 7.51-7.41 (m, 5H), 7.20-7.17 (m, 1H); ESMSclcd for C₂₀H₁₃F₃N₄O: 382.10. Found: 383.1 (M+H)⁺.

Compound 47

¹H-NMR (CDCl₃) δ (ppm) 8.1 (m, 2H), 8.0 (m, 1H), 7.72 (s, 1H), 7.6 (d,2H, J=8), 7.4 (m, 3H), 7.2 (m, 3H); ESMS clcd for C₁₃H₁₂F₅N₃: 425.1.Found: 426.1 (M+H)⁺.

Compound 69

¹H-NMR (CD₃OD) δ 8.6 (s, 1H), 8.15 (m, 1H), 7.86 (d, 1H, J=9), 7.42-7.60(m, 4H), 7.18-7.34 (m, 2H), 6.82 (d, 1H, J=1.5), 5.55-6.64 (m, 1H), 1.40(s, 9H) ppm; ESMS clod for C₂₆H₂₁F₃N₄O₃: 494.2. Found: 495.2 (M+H)⁺.

Compound 74

¹H-NMR (CDCl₃) δ (ppm) 8.44 (s, 1H), 8.20 (br, 1H), 8.0 (m, 6H), 7.6 (m,2H), 7.5 (d, 2H, J=8), 7.4 (d, 1H, J=2), 7.1 (m, 2H), 3.89 (s, 3H); ESMSclcd for C₂₆H₁₈F₃N₃O₂: 461.1. Found: 462.1 (MαH)⁺.

Compound 75

¹H-NMR (DMSO-d₆) δ (ppm) 10.3 (br, 1H), 8.1 (d, 2H, J=8), 7.6 (m, 1H),7.55 (s, 1H), 7.4 (d, 2H, J=8), 7.33 (s, 1H), 7.0 (m, 3H), 6.12 (s, 2H),3.86 (s, 3H); ESMS clcd for C₂₃H₁₆F₃N₃O₄: 455.1. Found: 456.1 (M+H)⁺.

Compound 77

¹H-NMR (CDCl₃) δ (ppm) 8.0 (m, 3H), 7.8 (m, 4H), 7.5 (d, 2H, J=8), 7.4(m, 1H), 7.0 (m, 2H), 3.89 (s, 3H); ESMS clcd for C₂₃H₁₅F₃N₄O₂: 436.1.Found: 437.1 (M+H)⁺.

Compound 79

¹H-NMR (DMSO-d₆) δ (ppm) 10.5 (br, 1H), 8.0 (d, 2H, J=9), 7.9 (d, 2H,J=8), 7.6 (d, 2H, J=9), 7.4 (m, 3H), 7.1 (m, 2H), 3.84 (s, 3H), 2.7 (q,2H, J=8), 1.2 (t, 3H, J=8); ESMS clcd for C₂₄H₂₀F₃N₃O₂: 439.1. Found:440.1 (M+H)⁺.

Compound 81

¹H-NMR (DMSO-d₆) δ (ppm) 11.2 (br, 1H), 9.2 (t, 2H, J=2), 9.0 (d, 1H,J=2), 8.1 (d, 2H, J=8), 7.6 (d, 2H, J=8), 743 (s, 1H), 7.1 (m, 2H), 3.84(s, 3H); ESMS clcd for C₂₂H₁₄F₃N₅O₆: 501.1. Found: 502.1 (M+H)⁺.

Compound 82

¹H-NMR (DMSO-d₆) δ (ppm) 10.2 (br, 1H), 7.8 (d, 2H, J=9), 7.5 (d, 2H,J=9), 7.4 (d, 1H, J=1), 7.1 (m, 2H), 3.83 (s, 3H), 2.3 (t, 2H, J=7), 1.6(m, 2H), 0.9 (t, 3H, J=7); ESMS clcd for C₁₉H₁₈F₃N₃O₂: 377.1. Found:378.1 (M+H)⁺.

Compound 83

¹H-NMR (DMSO-d₆) δ (ppm) 10.9 (br, 1H), 8.2 (m, 1H), 8.1 (m, 4H), 7.8(d, 1H, J=8), 7.6 (m, 5H), 7.4 (m, 1H), 7.1 (m, 2H), 3.85 (s, 3H); ESMSclod for C₂₆H₁₈F₃N₃O₂: 461.1. Found: 462.1 (M+H)⁺.

Compound 91

¹H-NMR (CDCl₃) δ (ppm) 7.8 (m, 3H), 7.5 (d, 2H, J=8), 7.4 (m, 1H), TO(m, 2H), 3.89 (s, 3H); ESMS clcd for C₂₂H₁₁F₈N₃O₂: 501.1. Found: 502.0(M+H).

Compound 99

¹H-NMR (CD₃OD) δ 7.99 (d, J=8.7 Hz, 2H), 7.50 (m, 4H), 7.65 (m, 1H),7.18 (d, J=2.1 Hz, 1H), 7.03 (m, 2H), 6.89 (t, J=6.9 Hz, 1H)

ESMS clcd for C₂₁H₁₂F₅N₃O₂: 433.1. Found: 434.1 (M+H)⁺.

Compound 101

¹H-NMR (DMSO-d₆) δ (ppm) 10.8 (br, 1H), 8.44 (s, 1H), 8.3 (d, 1H, J=6),8.1 (d, 1H, J=8), 8.0 (d, 2H, J=9), 7.8 (t, 1H, J=8), 7.6 (d, 2H, J=9),7.4 (d, 1H, J=2), 7.1 (m, 2H), 3.84 (s, 3H); ESMS clcd for C₂₃H₁₅F₃N₄O₂:436.1. Found: 437.1 (M+H)⁺.

Compound 105

¹H-NMR (DMSO-d₆) δ (ppm) 10.2 (br, 1H), 7.9 (d, 2H, J=9), 7.5 (d, 2H,J=9), 7.41 (s, 1H), 7.1 (m, 2H), 3.83 (s, 3H), 2.8 (m, 1H), 1.7 (m, 8H);ESMS clcd for C₂₁H₂₀F₃N₃O₂: 403.1. Found: 404.1 (M+H)⁺.

Compound 106

¹H-NMR (DMSO-d₆) δ (ppm) 10.2 (br, 1H), 7.8 (d, 2H, J=8), 7.5 (d, 2H,J=8), 7.4 (m, 1H), 7.1 (m, 2H), 3.83 (s, 3H), 2.4 (m, 1H), 1.8 (m, 4H),1.3 (m, 6H); ESMS clcd for C₂₂H₂₂F₃N₃O₂: 417.2. Found: 418.2 (M+H)⁺.

Compound 111

¹H-NMR (DMSO-d₅) δ (ppm) 10.6 (br, 1H), 8.0 (m, 4H), 7.6 (m, 5H), 7.4(d, 1H, J=2), 7.1 (m, 2H), 3.84 (s, 3H); ESMS clcd for C_(n)H₁₆F₃N₃O₂:411.1. Found: 412.1 (M+H)⁺.

Compound 112

¹H-NMR (CD₃OD) δ 8.5 (d, J=14.1 Hz, 1H), 7.94 (m, 3H), 7.40 (m, 5H),7.08 (m, 2H), 4.59 (m, 1H), 1.38 (d, J=6.3 Hz, 6H)

ESMS clcd for C₂₄H₁₅F₅N₃O₂: 475.1. Found: 476.1 (M+H)⁺.

Compound 114

¹H-NMR (DMSO-d₆) δ (ppm) 10.9 (br, 1H), 8.8 (m, 2H), 8.0 (m, 4H), 7.6(m, 2H), 7.4 (m, 1H), 7.1 (m, 2H), 3.84 (s, 3H); ESMS clcd forC₂₁H₁₅F₃N₄O₂: 412.1. Found: 413.1 (M+H)⁺.

Compound 116

¹H-NMR (DMSO-d₆) δ (ppm) 10.3 (br, 1H), 7.8 (d, 2H, J=9), 7.5 (d, 2H,J), 7.4 (m, 1H), U (m, 2H), 3.83 (s, 3H), 2.2 (d, 2H, J=7), 2.1 (m, 1H),0.9 (d, 6H, J=7); ESMS clcd for C₂₀H₂₀F₃N₃O₂: 391:2. Found: 392.1(M+H)⁺.

Isomeric Mixture 136

¹H NMR δ (DMSO-d₆) 8.06 (d, J=2.1. Hz, 1H), 7.95-7.98 (m, 2H), 7.48-715(m, 17H), 7.30-7.37 (m, 4H), 7.09 (d, J=9.3 Hz, 1H), 7.01 (d, J=2.1 Hz,1H); ESMS Calcd (C₂₈H₁₃ClF₇N₃O₂): 591.06. found (M+1) 592.1

H. Typical Synthesis of Compounds in which X is a Imidazo[1,2-a]pyridyl(Compound 70):

1.04 g (11 mmol) of 2-aminopyridine and 2.39 g (11 mmol) ofp-nitrobenzylbromide were dissolved in 20 mL CH₃CN. The solution waswarmed to reflux for 1 hr then cooled to room temperature, diluted withEt₂O, and the solid filtered, washed 4× with Et₂O and collected to yield3 g (88%) of 1-(4-Nitro-benzyl)-1H-pyridin-2-ylidene-ammonium bromide(174) as an off white solid.

To a solution of 1.01 g (3.27 mmol) of1-(4-Nitro-benzyl)-1H-pyridin-2-ylidene-ammonium bromide (174) and 4 mL1-methyl-2-pyrrolidinone (NMP) in a sealed tube was added 0.51 mL (3.6mmol) of trifluoroacetic anhydride and 0.96 mL (6.9 mmol) of triethylamine (TEA). The reaction mixture was heated to 155° C. for 3 hr thencooled to room temperature, diluted with 50 mL 2N NaOH and extracted 3times with 30 mL EtOAc. The combined organics were washed with saturatedaqueous NaHCO₃, and brine, dried over MgSO₄ filtered and concentrated invacuo. The crude oil was purified by silica gel chromatography 1:2(EtOAc:Hexanes) to yield 753 mg (74%) of3-(4-Nitro-phenyl)-2-trifluoromethyl-imidazo[1,2-a]pyridine (175) as ayellow solid.

To a solution of 690 mg (2.3 mmol) of3-(4-Nitro-phenyl)-2-trifluoromethyl-imidazo[1,2-a]pyridine (175) in 30mL of a 1:1 mixture of CH₂Cl₂ and ethanol (EtOH) was added 4.3 g (23mmol) of SnCl₂ and 4 drops of H₂O. The reaction was allowed to stirovernight at which time it was concentrated in vacuo, and the resultingoil dissolved in 40 mL of EtOAc and washed 3 times with 50 mL of 2NNaOH. The organic layer was then dried over MgSO₄ filtered andconcentrated in vacuo. 73 mg (0.26 mmol) of the resulting solid wasdissolved in 4 mL of CH₂Cl₂ to which 0.035 mL (0.27 mmol) of 3,4difluorobenzoylchloride and 0.09 mL (0.52 mmol) diisopropyl ethyl amine(DIPEA) were added. The reaction was allowed to stir for 4 hrs at whichtime it was diluted with 20 mL CH₂Cl₂, quenched with 15 mL saturatedaqueous NaHCO₃ and washed with 15 mL brine. The organic layer was thendried over MgSO₄ filtered and concentrated in vacuo. The crude oil waspurified by silica gel chromatography 1:3 (EtOAc:Hexanes) to yield 91 mg(84%) of2,3-Difluoro-N-[4-(2-trifluoromethyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-benzamide(Compound 70) as a white solid.

¹H-NMR (CDCl₃) δ 8.53 (d, J=10.8 Hz, 1H), 7.93 (m, 4H), 7.71 (d, J=9 Hz,1H), 7.52 (d, J=8.4 Hz, 2H), 7.42 (m, 3H), 6.89 (t, J=6.9 Hz, 1H)

ESMS clcd for C₂₁H₁₂F₅N₃O: 417.1. Found: 418.3 (M+H)⁺.

1. Synthesis of Compound 8

A mixture of (substituted)-2-Picoline (10.73 mmols) (177) andp-nitrobenzylbromide (10.73 mmols) (178) was stirred overnight in 10 mLof acetonitrile at room temperature. The white solid obtained wasfiltered, washed with acetonitrile and dried to afford 179 in 50%-95%yields.

A mixture of the salt 179 (3.23 mmols), ethyltrifluoroacetate 180 (3.23mmols) and DBU (6.47 mmols) in 5 mL of anhydrous NMP was heated in apressure tube at 130-140° C. for 0.5-8 h. The tube was cooled, thecontents were poured into 100 mL of water and the product was extractedwith ethyl acetate (15 mL×3). The combined extracts were washed withbrine and dried over anhydrous Na₂SO₄. Concentration followed by columnchromatography on silica gel using a mixture of hexane/EtOAc to affordthe cyclized product 181 in 10%-80% yields.

To a stirred solution of 181 (1.31 mmols) in 20 mL of 1:1 CH₂Cl₂:EtOH,was added of SnCl₂ (13.06 mmols) followed by a few drops of water. Themixture was stirred overnight and concentrated. To the residue, wasadded 20 mL of water and the solution the brought to pH˜8-9 using 2NNaOH. The resulting mixture was successively extracted with ethylacetate (20 mL×4), washed with brine (20 mL) and dried over Na₂SO₄.Concentration on Rota vapor afforded 182 in 70-97% yields.

To a solution of 182 (0.30 mmols) in 5 mL of CH₂Cl₂, was added thecorresponding acyl chloride 183 (0.30 mmols), followed bydiisopropyl-ethylamine (0.60 mmols). The resultant mixture was stirredat room temperature for 30 min and eluted through a short pad of silicagel using mixture of hexane:ethyl acetate to afford the product 184 in80-96% yields.

To a solution of 400 mg (1.3 mmol) of3-(4-Nitro-phenyl)-2-trifluoromethyl-indolizine in 12 mL MeOH was added200 mg (10%) Pd/C. The solution was allowed to stir under a H₂atmosphere for 24 hrs then filtered through celite and concentrated invacuo. The resulting oil was purified by silica gel chromatographyHexane:EtOAc (gradient 9:1-1:1) to yield 300 mg (1.1 mmol, 85%) of4-(2-Trifluoromethyl-5,6,7,8-tetrahydro-indolizin-3-yl)-phenylamine.

Compound 8 was then synthesized from4-(2-Trifluoromethyl-5,6,7,8-tetrahydro-indolizin-3-yl)-phenylamine and2,3-difluorobenzoyl chloride in a similar manner as described in Methods1 or 2.

¹H-NMR (CDCl₃) δ 8.41 (d, J=10.8 Hz, 1H), 7.93 (m, 1H), 7.70 (d, J=8.4Hz, 2H), 7.35 (m, 3H), 7.24 (m, 1H), 6.12 (s, 1H), 3.66 (t, J=6.0 Hz,2H), 2.82 (t, J=6 Hz, 2H), 1.9 (m, 4H).

ESMS clcd for C₂₂H₁₇F₅N₂O: 420.13. Found: 421.4 (M+H)⁺.

Compound 24

Compound 24 was prepared in a similar method as described for Compound8.

¹H-NMR (CDCl₃) δ 8.59 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4Hz, 2H), 6.25 (s, 1H), 3.76 (t, J=6.0 Hz, 2H), 3.07 (s, 3H), 2.92 (t,J=6 Hz, 2H), 1.9 (m, 4H).

ESMS clcd for C₁₉H₁₇F₃N₄OS: 406.1. Found: 407.1 (M+H)⁺.

J. Synthesis of Compound 44

A suspension of a substituted imidazo[4,5-b]pyridyl (27 mmol) andpotassium t-butoxide (3.6 g, 30 mmol) in DMF (50 mL) was stirred at roomtemperature for 30 min. 1-Fluoro-4-nitro-benzene (4.2 g, 30 mmol) wasadded and the reaction mixture was heated to 150° C. for 4 h. Thereaction mixture was diluted with water and extracted with ethyl acetate(EtOAc). The organic extract was washed with water and dried. The oilobtained on concentration was flash chromatographed on silica gel togive 185 in 10-90% yields.

A stirred suspension of compound 185 (12 mmol) in EtOAc (100 mL) and 10%Pd—C (150 mg) was attached to a H₂ balloon for 4-12 h. The mixture wasfiltered through celite and concentrated to give compound 186.

To a mixture of compound 186 (4.0 mmol) and pyridine (1.3 mL) inchloroform (50 mL) at room temperature was added an acid chloride (5.0mmol). The reaction mixture was stirred for 2-12 h. The reaction mixturewas diluted with 1N HCl, extracted with chloroform and dried. Theresidue obtained on concentration was crystallized from EtOAc/hexane orflash chromatographed to give the product Compound 44 in 30%-95% yield.

¹H-NMR (CD₃OD) δ 8.45-8.55 (m, 2H), 8.25 (d, 1H, J=8), 7.85-7.95 (m,3H), 7.35-7.55 (m, 4H), 7.15-7.30 (m, 1H) ppm; ESMS clcd forC₂₀H₁₁F₅N₅O₄: 418.0. Found: 419.0 (M+H)⁺.

K. Synthesis of Compounds 187, 188, and 189

To a solution of 4-chloro3-nitroanisole (190, 26.7 mmol) and1,4-phenylenediamine (191, 134.1 mmol) in DMF (100 mL) was added K₂CO₃(11 g, 79.6 mmol). The reaction mixture was refluxed at 120° C. for 48h. The solution was allowed to cool to room temperature then ice wasadded. The solution was washed with H₂O (6×60 mL) and the combinedaqueous phase was extracted with ethyl acetate (EtOAc) (2×100 mL). Thecombined organic phase was washed with H₂O (3×100 mL), dried overNa_(z)SO₄, and concentrated. The concentrate was purified by flashcolumn chromatography (Hexanes:EtOAc=3:1) and afforded 192 as dark brownsolid (2.4 g, 35%).

A flask containing a solution of 192 (1.5 g) and Pd/C (200 mg) in 20 mLEtOAc was charged with hydrogen using a hydrogen balloon. The reaction,was stirred overnight then filtered. The filtrate was concentrated andthe residue was dissolved in trifluoroacetic acid (TFA) (10 mL, 129.8mmol) and trifluoroacetic anhydride (TFAA) (2 mL, 14.4 mmol). Theresulting solution was refluxed for 2.5 h and then diluted with EtOAc(50 mL) and neutralized with saturated aqueous NaHCO₃. The organic phasewas dried over Na₂SO₄, filtered, and concentrated. The residue was thendissolved in MeOH (40 mL) and to the solution was added K₂CO₃ (3.5 g,25.3 mmol). The solution was refluxed at 80° C. for 20 h before it wasfiltered and concentrated. The concentrate was purified by columnchromatography (Hexanes:EtOAc=3:1) to afford 193 (1.5 g).

To a solution of 193 (1.5 g, 4.88 mmol) in EtOH (50 mL) was added2,6-difluorobenzylaldehyde (1.1 mL, 10.1 mmol) at room temperature inone shot. After 3 h, NaBH₄ (1.1 g, 29.1 mmol) was added to the solution.The reaction solution was stirred overnight and then extracted withH₂O/EtOAc. The organic layer was concentrated and the concentrate waspurified by column chromatography (Hexanes:EtOAc=5:1) to afford compound187 (1.9 g).

¹H-NMR (CDCl₃) δ (ppm) 7.32-7.15 (m, 5H), 7.02-6.91 (m, 4H), 6.82-6.78(m, 1H), 4.42 (m, 2H), 3.85 (s, 3H); ESMS cacld (C₂₂H₁₆F₅N₃O): 433.1.Found: 434.1 (M+H).

To a solution of compound 187 (400 mg, 0.96 mmol) in MeOH (1 mL) wasadded benzenesulfonic acid (148 mg, 0.94 mmol). The solution wasrecrystallized by adding ether and the filtration gave compound 188 aswhite solid (250 mg).

¹H-NMR (CDCl₃) δ (ppm) 7.92-7.88 (m, 2H), 7.48-7.24 (m, 8H), 7.09-6.79(m, 6H), 4.71 (s, 2H), 3.86 (s, 3H); ESMS calcd (C₂₂H₁₆F₅N₃O): 433.1.Found: 434.0 (M+H).

To a solution of compound 187 (259 mg, 0.60 mmol) in MeOH (2 mL) wasadded a solution of sulfuric acid (0.04 mL, 0.75 mmol) in 1 mL MeOH. Theresulting solution was stirred at room temperature for 1 h before it wasconcentrated. Recrystallization (MeOH/ether) gave compound 189 as awhite solid (220 mg).

¹H-NMR ((CD₃)₂SO) δ (ppm) 7.48-7.35 (m, 2H), 7.22-7.00 (m, 6H),6.79-6.77 (m, 2H), 6.61 (brs, 2H), 4.29 (s, 2H), 3:79 (s, 3H); ESMScalcd (C₂₂H₁₆F₅N₃O): 433.1. Found: 434.1 (M+H).

Representative Analytical Data for Other Exemplary Compounds of thisInvention Compound 1: Found: 465.4 (M+H)⁺. Compound 2: Found: 465.4(M+H)⁺. Compound 4: Found: 447.4 (M+H)⁺. Compound 5: Found: 4264 (M+H)⁺.Compound 7: Found: 498.3 (M+H)⁺. Compound 10: Found: 456.4 (M+H)⁺.Compound 12: Found: 433.4 (M+H)⁺. Compound 13: Found: 450.2 (M+H)⁺.Compound 14: Found: 447.4 (M+H)⁺. Compound 15: Found: 433.8 (M+H)⁺.Compound 16: Found: 450.3 (M+H)⁺. Compound 17: Found: 431.4 (M+H)⁺.Compound 18: Found: 498.4 (M+H)⁺. Compound 19: Found: 420.4 (M+H)⁺.Compound 20: Found: 442.3 (M+H)⁺. Compound 23: Found: 383.8 (M+H)⁺.Compound 25: Found: 451.8 (M+H)⁺. Compound 26: Found: 417.3 (M+H)⁺.Compound 28: Found: 428.2 (M+H)⁺. Compound 29: Found: 403.4 (M+H)⁺.Compound 30: Found: 485.3 (M+H)⁺. Compound 31: Found: 532.5 (M+H)⁺.Compound 32: Found: 477.4 (M+H)⁺. Compound 33: Found: 475.2 (M+H)⁺.Compound 35: Found: 473.4 (M+H)⁺. Compound 36: Found: 418.3 (M+H)⁺.Compound 37: Found: 442.3 (M+H)⁺. Compound 38: Found: 451.8 (M+H)⁺.Compound 39: Found: 432.4 (M+H)⁺. Compound 40: Found: 411.4 (M+H)⁺.Compound 41: Found: 418.3 (M+H)⁺. Compound 42: Found: 445.4 (M+H)⁺.Compound 43: Found: 432.4 (M+H)⁺. Compound 46: Found: 417.3 (M+H)⁺.Compound 48: Found: 425.4 (M+H)⁺. Compound 49: Found: 391.4 (M+H)⁺.Compound 50: Found: 432.4 (M+H)⁺. Compound 51: Found: 416.3 (M+H)⁺.Compound 52: Found: 453.4 (M+H)⁺. Compound 53: Found: 474.4 (M+H)⁺.Compound 54: Found: 349.3 (M+H)⁺. Compound 55: Found: 431.4 (M+H)⁺.Compound 56: Found: 418.3 (M+H)⁺. Compound 57: Found: 562.5 (M+H)⁺.Compound 58: Found: 357.4 (M+H)⁺. Compound 59: Found: 363.4 (M+H)⁺.Compound 60: Found: 449.3 (M+H)⁺. Compound 61: Found: 418.3 (M+H)⁺.Compound 62: Found: 404.4 (M+H)⁺. Compound 63: Found: 514.7 (M+H)⁺.Compound 64: Found: 485.3 (M+H)⁺. Compound 65: Found: 495.4 (M+H)⁺.Compound 66: Found: 467.5 (M+H)⁺. Compound 67: Found: 540.5 (M+H)⁺.Compound 68: Found: 540.5 (M+H)⁺. Compound 71: Found: 483.3 (M+H)⁺.Compound 72: Found: 487.5 (M+H)⁺. Compound 73: Found: 537.3 (M+H)⁺.Compound 76 Found: 425.4 (M+H)⁺. Compound 78: Found: 456.4 (M+H)⁺.Compound 80: Found: 479.4 (M+H)⁺. Compound 84: Found: 389.4 (M+H)⁺.Compound 85: Found: 453.5 (M+H)⁺. Compound 86: Found: 417.4 (M+H)⁺.Compound 87: Found: 433.5 (M+H)⁺. Compound 88: Found: 419.4 (M+H)⁺.Compound 89: Found: 441.4 (M+H)⁺. Compound 90: Found: 451.4 (M+H)⁺.Compound 92: Found: 455.4 (M+H)⁺. Compound 93: Found: 474.4 (M+H)⁺.Compound 94: Found: 431.4 (M+H)⁺. Compound 95: Found: 425.4 (M+H)⁺.Compound 97: Found: 501.3 (M+H)⁺. Compound 98: Found: 447.4 (M+H)⁺.Compound 100: Found: 447.4 (M+H)⁺. Compound 102: Found: 480.3 (M+H)⁺.Compound 103: Found: 447.4 (M+H)⁺. Compound 104: Found: 490.3 (M+H)⁺.Compound 107: Found: 456.4 (M+H)⁺. Compound 108: Found: 445.8 (M+H)⁺.Compound 109: Found: 445.8 (M+H)⁺. Compound 110: Found: 447.4 (M+H)⁺.Compound 113: Found: 460.4 (M+H)⁺. Compound 115: Found: 537.3 (M+H)⁺.Compound 117: Found: 480.3 (M+H)⁺. Compound 118: Found: 490.3 (M+H)⁺.Compound 119: Found: 490.3 (M+H)⁺. Compound 120: Found: 401.3 (M+H)⁺.Compound 121: Found: 500.4 (M+H)⁺. Compound 122: Found: 361.3 (M+H)⁺.Compound 123: Found: 455.4 (M+H)⁺. Compound 124: Found: 457.5 (M+H)⁺.Compound 125: Found: 435.4 (M+H)⁺. Compound 126: Found: 445.8 (M+H)⁺.Compound 127: Found: 547.4 (M+H)⁺. Compound 128: Found: 441.4 (M+H)⁺.Compound 129: Found: 547.4 (M+H)⁺. Compound 130: Found: 485.5 (M+H)⁺.Compound 131: Found: 485.5 (M+H)⁺. Compound 132: Found: 475.4 (M+H)⁺.Compound 133: Found: 459.4 (M+H)⁺. Compound 135: Found: 469.8 (M+H)⁺.Example 2 Inhibition of IL-2 Production

Jurkat cells were placed in a 96 well plate (0.5 million cells per wellin 1% FBS medium) then test compounds of this invention were added atdifferent concentrations. After 10 minutes, the cells were activatedwith PHA (final concentration 2.5 μg/mL) and incubated for 20 hours at37° C. under CO₂. The final volume was 200 μL. Following incubation, thecells were centrifuged and the supernatants collected and stored at −70°C. prior to assaying for IL-2 production. A commercial kit (IL-2Eli-pair, Diaclone Research, Besancon, France) was used to detectproduction of IL-2, from which dose response curves were obtained. TheIC₅₀ value was calculated as the concentration at which. 50% of maximumIL-2 production after stimulation was inhibited versus a non-stimulationcontrol.

IC₅₀ Compounds   <100 nM 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,71, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 132, 135, 187 100-500nM 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 63, 64, 65, 66, 69, 70, 72, 73, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 133,134, 136 500 nM-1 μM 41, 42, 43, 44, 45, 46, 47, 48, 56, 91, 92, 93, 94,95    >1 μM 49, 50, 51, 52, 53, 54, 55, 57, 58, 59, 60, 61, 62, 67, 68,120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131

Example 3 Activation of TRPM4 Channel

TRPM4 currents were measured in Jurkat cells and HEK-293 cellsoverexpressing TRPM4. The external solution contained the following(mM): NaCl 140, KCl 2.8, MgCl₂ 2, CaCl₂ 1, glucose 10, and HEPES.NaOH 10(ph 7.2). The internal solution contained the following (mM):K-glutamate 120, NaCl 8, MgCl₂ 1, K.BAPTA 10, HEPES.CsOH 10 (ph 7.2).Ramps were given every 2 s (−100 to +100 mV in 50 ms) and cells wereheld at −80 mV between ramps. Free intracellular calcium was adjusted to300 nM.

Representative compounds of this invention, including Compounds 9, werefound to activate TRPM4 channels using this method.

Example 4 Patch Clamp Studies of Inhibition of I_(CRAC) Current in RBLCells, Jurkat Cells, and Primary T Cells

In general, a whole cell patch clamp method was used to examine theeffects of a compound of the invention on a channel that mediatesI_(crac). In such experiments, a baseline measurement was establishedfor a patched cell. Then a compound to be tested was perfused (orpuffed) to cells in the external solution and the effect of the compoundon I_(crac) was measured. A compound that modulates I_(crac) (e.g.,inhibits) is a compound that is useful in the invention for modulatingCRAC ion channel activity.

1) RBL Cells

Cells

Rat basophilic leukemia cells (RBL-2H3) were grown in DMEM mediasupplemented with 10% fetal bovine serum in an atmosphere of 95% air/5%CO₂. Cells were seeded on glass coverslips 1-3 days before use.

Recording Conditions

Membrane currents of individual cells were recorded using the whole-cellconfiguration of the patch clamp technique with an EPC10 (HEKAElectronik, Lambrecht, Germany). Electrodes. (2-5 MΩ in resistance) werefashioned from borosilicate glass capillary tubes (Sutter Instruments,Novato, Ca). The recordings were done at room temperature.

Intracellular Pipette Solution

Cs-Glutamate 120 mM; CsCl 20 mM; CsBAPTA 10 mM; CsHEPES 10 mM; NaCl 8mM; MgCl₂ 1 mM; IP3 0.02 mM; pH=7.4 adjusted with CsOH. (Shielded fromlight and kept on ice before experiment)

Extracellular Solution

NaCl 138 mM; NaHEPES, 10 mM; CsCl 10 mM; CaCl₂ 10 mM; Glucose 5.5 mM;KCl 5.4 mM; KH₂PO₄ 0.4 mM; Na₂HPO₄.H₂O 0.3 mM at pH=7.4 adjusted withNaOH.

Compound Treatment

Each compound was diluted from a 10 mM stock in series using DMSO (10μM, 3.2 μM, 0.1 μM, 316 nM, 100 nM 32 nM). The final DMSO concentrationwas always kept at 0.1%.

Experimental Procedure

I_(crac) currents were monitored every 2 seconds using a 50 msecprotocol, where the voltage was ramped from −100 mV to +100 mV. Themembrane potential was held at 0 mV between the test ramps. In a typicalexperiment the peak inward currents would develop within 50-100 seconds.Once the I_(CRAC) currents were stabilized, the cells were perfused withcompounds in the extracellular solution. At the end of an experiment theremaining I_(CRAC) currents were then challenged with a control compound(SKF96365, 10 μM) to ensure that the current could still be inhibited.

Data Analysis

The I_(CRAC) current level was determined by measuring the inwardcurrent amplitude at −80 mV of the voltage ramp in an off-line analysisusing MATLAB. The I_(CRAC) current inhibition, for each concentrationwas calculated using peak amplitude in the beginning of the experimentfrom the same cell. The IC₅₀ value and Hill coefficient for eachcompound was estimated by fitting all the individual data points to asingle Hill equation.

2) Jurkat Cells

Cells

Jurkat T cells were grown on glass coverslips, transferred to therecording chamber and kept in a standard modified Ringers solution ofthe following composition: NaCl 145 mM, KCl 2.8 mM, CsCl 10 mM, CaCl₂ 10mM, MgCl₂ 2 mM, glucose 10 mM, HEPES.NaOH 10 mM, pH 7.2.

Extracellular Solution

The external solution contained 10 mM CaNaR, 11.5 mM glucose and thetest compound at the concentrations described below.

Intracellular Pipette Solution

The standard intracellular pipette solution contained: Cs-glutamate 145mM, NaCl 8 mM, MgCl₂ 1 mM, ATP 0.5 mM, GTP 0.3 mM, pH 7.2 adjusted withCsOH. The solution was supplemented with a mixture of 10 mM Cs-BAPTA and4.3-5.3 mM CaCl₂ to buffer [Ca²⁺i to resting levels of 100-150 nM.

Patch-Clamp Recordings

Patch-clamp experiments were performed in the tight-seal whole-cellconfiguration at 21-25° C. High-resolution current recordings wereacquired by a computer-based patch-clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Sylgard®-coated patch pipettes had resistancesbetween 2-4 MΩ after filling with the standard intracellular solution.Immediately following establishment of the whole-cell configuration,voltage ramps of 50 ms duration spanning the voltage range of −100 to+100 mV were delivered from a holding potential of 0 mV at a rate of 0.5Hz over a period of 300 to 400 seconds. All voltages were corrected fora liquid junction potential of 10 mV between external and internalsolutions. Currents were filtered at 2.3 kHz and digitized at 100 μsintervals. Capacitive currents and series resistance were determined andcorrected before each voltage ramp using the automatic capacitancecompensation of the EPC-9.

Data Analysis

The very first ramps before activation of O_(CRAC) (usually 1 to 3) weredigitally filtered at 2 kHz, pooled and used for leak-subtraction of allsubsequent current records. The low-resolution temporal development ofinward currents was extracted from the leak-corrected individual rampcurrent records by measuring the current amplitude at −80 mV or avoltage of choice.

3) Primary T Cells

Preparation of Primary T Cells

Primary T cells were obtained from human whole blood samples by adding100 μL of RosetteSep® human T cell enrichment cocktail to 2 mL of wholeblood. The mixture was incubated for 20 minutes at room temperature,then diluted, with an equal volume of PBS containing 2% FBS. The mixturewas layered on top of RosetteSep® DM-L density medium and thencentrifuged for 20 minutes at 1200 g at room temperature. The enriched Tcells were recovered from the plasma/density medium interface, thenwashed with PBS containing 2% FBS twice, and used in patch clampexperiments following the procedure described for RBL cells.

Results:

Certain compounds of the invention were found to decrease I_(CRAC)current.

Example 5 Patch Clamp Studies of Inhibition of Kv1.3 in Jurkat T Cells

Cells

Jurkat T cells were grown on glass coverslips, transferred to therecording chamber and kept in a standard modified Ringer's solution ofthe following composition: NaCl 145 mM, KCl 2.8 mM, CsCl 10 mM, CaCl₂ 10mM, MgCl₂ 2 mM, glucose 10 mM, HEPES NaOH 10 mM, pH 7.2.

Extracellular Solution

The external solution contained 1 mM CaCl₂, 140 mM NaCl, 2.8 mM KCl, 2mM MgCl₂ and the test compound at the concentrations described below.

Intracellular Pipette Solution

The standard intracellular pipette solution contained: 140 mM potassiumglutamate, 8 mM NaCl, 1 mM MgCl2, 10 mM potassium bapta, 10 mMHepes-KOH.

Patch-Clamp Recordings

Patch-clamp experiments were performed in the tight-seat whole-cellconfiguration at 21-25° C. High-resolution current recordings wereacquired by a computer-based patch-clamp amplifier system (EPC-9, HEKA,Lambrecht, Germany). Sylgard®-coated patch pipettes had resistancesbetween 2-4 MΩ after filling with the standard intracellular solution.Immediately following establishment of the whole-cell configuration,voltage ramps of 50 ms duration spanning the voltage range of −80 to +80mV were delivered from a holding potential of 0 mV at a rate of 0.5 Hzover a period of 300 to 400 seconds.

Results

Certain compounds of the invention, including Compound 1, were found toinhibit Kv1.3 in Jurkat T cells.

Example 6 Inhibition of Multiple Cytokines in Primary Human PBMCs

Peripheral blood mononuclear cells (PBMCs) were stimulated withphytohemagglutinin (PHA) in the presence of varying concentrations ofcompounds of the invention or cyclosporine A (CsA), a known inhibitor ofcytokine production. Cytokine production was measured using commerciallyavailable human ELISA assay kits (from Cell Science, Inc.) following themanufacturers instructions.

Table 2 shows the concentration of CsA and compounds 1 and 135 whichinhibit 50% of a cytokine production. As can be seen from the data,compounds 31, 66, and 75 are potent inhibitors of IL-2, IL-4, IL-5,IL-13, GM-CSF, INF-γ and TNF-α. In addition, compounds of the inventiondo not inhibit the anti-inflammatory cytokine, IL-10.

TABLE 2 IC₅₀ values for cytokine inhibition. Cpd # IL-2 IL-4 IL-5 IL-10IL-13 GM-CSF INF-γ TNF-α CsA 3 25 7 948 67 109 18 26  1 29 651 26 >100073 788 95 424 135 3 101 13 439 25 99 29 47

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting in any way.

1. A method of inhibiting immune cell activation comprisingadministering to the cell a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof wherein: X is anoptionally substituted 5,6,7,8-tetrahydroindolizinyl; Y is anunsubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heteroaryl, or anoptionally substituted heteroaralkyl; A is —O—, —S(O)_(p)—, —NH—, —NZ—,—CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, oran N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—; Z, for each occurrence,is independently selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo, —OR₄, cyano, nitro,haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂,—OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂; L is a linkerselected from the group consisting of an optionally substituted loweralkyl, and optionally substituted lower alkenyl, —NRCR₄R₅—, —C(O)—,—OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—,—NR—S(O)_(h)—, —S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—,—NR—C(═N—CN)—NR—, —NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or—NR—C(S)—NR—; R, for each occurrence, is independently selected from —H,an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl; R₁ and R₂, foreach occurrence are, independently, H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁and R₂ taken together with the nitrogen to which they are attached isoptionally substituted heterocyclyl or optionally substitutedheteroaryl; R₄ and R₅ for each occurrence are, independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; h is 1 or 2; n is 0 or an integer from 1 to 4;and p, for each occurrence, is, independently, 0, 1, or
 2. 2. The methodof claim 1, wherein immune cell activation is inhibited in a subject byadministering the compound to the subject.
 3. The method of claim 2,wherein the subject is human.
 4. A method of inhibiting cytokineproduction in a cell, comprising administering to the cell a compoundrepresented by formula (I):

or a pharmaceutically acceptable salt: X is an optionally substituted5,6,7,8-tetrahydroindolizinyl; Y is an unsubstituted alkyl, anoptionally substituted alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substituted aryl, anoptionally substituted heteroaryl, or an optionally substitutedheteroaralkyl; A is —O—, —S(O)_(p)—, —NH—, —NZ—, —CH═CH—, —CZ═CH—,—CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of—N═CH—, —N═CZ—, —CH═N—, or —CZ═N—; Z, for each occurrence, isindependently selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo, —OR₄, cyano, nitro,haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂,—OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂; L is a linkerselected from the group consisting of an optionally substituted loweralkyl, and optionally substituted lower alkenyl, —NRCR₄R₅—, —C(O)—,—OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—,—NR—S(O)_(h)—, —S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—,—NR—C(═N—CN)—NR—, —NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or—NR—C(S)—NR—; R, for each occurrence, is independently selected from —H,an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl; R₁ and R₂, foreach occurrence are, independently, H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁and R₂ taken together with the nitrogen to which they are attached isoptionally substituted heterocyclyl or optionally substitutedheteroaryl; R₄ and R₅ for each occurrence are, independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; h is 1 or 2; n is 0 or an integer from 1 to 4;and p, for each occurrence, is, independently, 0, 1, or
 2. 5. The methodof claim 4, wherein cytokine production is inhibited in a subject byadministering the compound to the subject.
 6. The method of claim 5,wherein the subject is human.
 7. The method of claim 4, wherein thecytokine which is inhibited is selected from the group consisting ofIL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-γ, TNF-α, and combinations thereof.8. A method of modulating an ion channel in a cell, wherein the ionchannel is involved in immune cell activation, comprising administeringto the cell a compound represented by formula (I):

or a pharmaceutically acceptable salt wherein: X is an optionallysubstituted 5,6,7,8-tetrahydroindolizinyl; Y is an unsubstituted alkyl,an optionally substituted alkenyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substituted aryl,an optionally substituted heteroaryl, or an optionally substitutedheteroaralkyl; A is —O—, —S(O)_(p)—, —NH—, —NZ—, —CH═CH—, —CZ═CH—,—CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, or an N-oxide of—N═CH—, —N═CZ—, —CH═N—, or —CZ═N—; Z, for each occurrence, isindependently selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo, —OR₄, cyano, nitro,haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂,—OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂; L is a linkerselected from the group consisting of an optionally substituted loweralkyl, and optionally substituted lower alkenyl, —NRCR₄R₅—, —C(O)—,—OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—,—NR—S(O)_(h)—, —S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—,—NR—C(═N—CN)—NR—, —NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or—NR—C(S)—NR—; R, for each occurrence, is independently selected from —H,an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl; R₁ and R₂, foreach occurrence are, independently, H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁and R₂ taken together with the nitrogen to which they are attached isoptionally substituted heterocyclyl or optionally substitutedheteroaryl; R₄ and R₅ for each occurrence are, independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; h is 1 or 2; n is 0 or an integer from 1 to 4;and p, for each occurrence, is, independently, 0, 1, or
 2. 9. The methodof claim 8, wherein the ion channel is in a subject and it is modulatedby administering the compound to the subject.
 10. The method of claim 9,wherein the subject is human.
 11. The method of claim 8, wherein the ionchannel is a CRAC ion channel.
 12. The method of claim 8, wherein theion channel is a TRPM4 or Kv1.3 ion channel.
 13. A method of inhibitingimmune cell proliferation in response to an antigen, comprisingadministering to the cell a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof wherein: X is anoptionally substituted 5,6,7,8-tetrahydroindolizinyl; Y is anunsubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heteroaryl, or anoptionally substituted heteroaralkyl; A is —O—, —S(O)_(p)—, —NH—, —NZ—,—CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, oran N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—; Z, for each occurrence,is independently selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo, —OR₄, cyano, nitro,haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂,—OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂; L is a linkerselected from the group consisting of an optionally substituted loweralkyl, and optionally substituted lower alkenyl, —NRCR₄R₅—, —C(O)—,—OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—,—NR—S(O)_(h)—, —S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—,—NR—C(═N—CN)—NR—, —NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or—NR—C(S)—NR—; R, for each occurrence, is independently selected from —H,an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl; R₁ and R₂, foreach occurrence are, independently, H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁and R₂ taken together with the nitrogen to which they are attached isoptionally substituted heterocyclyl or optionally substitutedheteroaryl; R₄ and R₅ for each occurrence are, independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; h is 1 or 2; n is 0 or an integer from 1 to 4;and p, for each occurrence, is, independently, 0, 1, or
 2. 14. Themethod of claim 13, wherein immune cell proliferation is inhibited in asubject by administering the compound to the subject.
 15. The method ofclaim 14, wherein the immune cell is a T-cell, B-cell, and/or mast cell.16. The method of claim 14, wherein the subject is human.
 17. A methodfor treating or preventing an immune disorder in a subject in needthereof, comprising administering to the subject an effective amount ofa compound represented by formula (I):

or a pharmaceutically acceptable salt thereof wherein: X is anoptionally substituted 5,6,7,8-tetrahydroindolizinyl; Y is anunsubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heteroaryl, or anoptionally substituted heteroaralkyl; A is —O—, —S(O)_(p)—, —NH—, —NZ—,—CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, oran N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—; Z, for each occurrence,is independently selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo, —OR₄, cyano, nitro,haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂,—OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂; L is a linkerselected from the group consisting of an optionally substituted loweralkyl, and optionally substituted lower alkenyl, —NRCR₄R₅—, —C(O)—,—OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —C(S)—,—NR—S(O)_(h)—, —S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—,—NR—C(═N—CN)—NR—, —NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or—NR—C(S)—NR—; R, for each occurrence, is independently selected from —H,an alkyl, acetyl, alkoxycarbonyl, or aralkoxycarbonyl; R₁ and R₂, foreach occurrence are, independently, H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₁and R₂ taken together with the nitrogen to which they are attached isoptionally substituted heterocyclyl or optionally substitutedheteroaryl; R₄ and R₅ for each occurrence are, independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; h is 1 or 2; n is 0 or an integer from 1 to 4;and p, for each occurrence, is, independently, 0, 1, or 2; wherein thedisorder is selected from the group consisting of multiple sclerosis,myasthenia gravis, Guillain-Barré, autoimmune uveitis, autoimmunehemolytic anemia, pernicious anemia, autoimmune thrombocytopenia,temporal arteritis, anti-phospholipid syndrome, vasculitides such asWegener's granulomatosis, Behcet's disease, psoriasis, dermatitisherpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, ulcerativecolitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 orimmune-mediated diabetes mellitus, Grave's disease. Hashimoto'sthyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder ofthe adrenal gland, rheumatoid arthritis, systemic lupus erythematosus,scleroderma, polymyositis, dermatomyositis, ankylosing spondylitis, andSjogren's syndrome.
 18. The method of claim 17, wherein the subject ishuman.
 19. (canceled)
 20. A method for treating or preventing aninflammatory condition in a subject in need thereof, comprisingadministering to the subject an effective amount of a compoundrepresented by formula (I):

or a pharmaceutically acceptable salt thereof wherein: X is anoptionally substituted 5,6,7,8-tetrahydroindolizinyl; Y is anunsubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heteroaryl, or anoptionally substituted heteroaralkyl; A is —O—, —S(O)_(p)—, —NH—, —NZ—,—CH═CH—, —CZ═CH—, —CH═CZ—, —CZ═CZ—, —N═CH—, —N═CZ—, —CH═N—, —CZ═N—, oran N-oxide of —N═CH—, —N═CZ—, —CH═N—, or —CZ═N—; Z, for each occurrence,is independently selected from the group consisting of an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₁R₂, —NR₄C(O)R₅, halo, —OR₄, cyano, nitro,haloalkoxy, —C(O)R₄, —NR₁R₂, —C(O)OR₄, —OC(O)R₄, —NR₄C(O)NR₁R₂,—OC(O)NR₁R₂, —NR₄C(O)OR₅, —S(O)_(p)R₄, or —S(O)_(h)NR₁R₂; L is a linkerselected from the group consisting of an optionally substituted loweralkyl, and optionally substituted lower alkenyl, —NRCR₄R₅—, —C(O)—,—OC(O)—, —C(O)O—, —NR—C(O)—, —C(O)—NR—, —NR—C(O)—NR—, —NR—S(O)_(h)—,—S(O)_(h)—NR—, —NR—C(═NR)—, —NR—C(═NR)—NR—, —NR—C(═N—CN)—NR—,—NR—C(═N—NO₂)—NR—, —NR—C(S)—, —C(S)—NR—, or —NR—C(S)—NR—; R, for eachoccurrence, is independently selected from —H, an alkyl, acetyl,alkoxycarbonyl, or aralkoxycarbonyl; R₁ and R₂, for each occurrence are,independently, H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₁ and R₂ taken together withthe nitrogen to which they are attached is optionally substitutedheterocyclyl or optionally substituted heteroaryl; R₄ and R₅ for eachoccurrence are, independently, H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; h is 1or 2; n is 0 or an integer from 1 to 4; and p, for each occurrence, is,independently, 0, 1, or 2; wherein the disorder is selected fromtransplant rejection; arthritis, rheumatoid arthritis, osteoarthritisand bone diseases associated with increased bone resorption;inflammatory bowel disease, ileitis, ulcerative colitis, Barrett'ssyndrome, Crohn's disease; asthma, adult respiratory distress syndrome,chronic obstructive airway disease; corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis, endophthalmitis;gingivitis, periodontitis; tuberculosis; leprosy; uremic complications,glomerulonephritis, nephrosis; sclerodermatitis, psoriasis, eczema;chronic demyelinating diseases of the nervous system, multiplesclerosis, AIDS-related neurodegeneration, Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis viral or autoimmuneencephalitis; autoimmune disorders, immune-complex vasculitis, systemiclupus and erythematodes; systemic lupus erythematosus (SLE);cardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis, preeclampsia; chronic liver failure, brain and spinalcord trauma, and cancer.
 21. The method of claim 20, wherein the subjectis human. 22-58. (canceled)